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Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease.
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Investigación Biomédica , Pruebas Genéticas/normas , Variación Genética/genética , Genómica/métodos , Laboratorios/normas , Mutación/genética , Análisis de Secuencia de ADN/normas , Interpretación Estadística de Datos , Práctica Clínica Basada en la Evidencia , Exoma/genética , Genoma Humano , Guías como Asunto , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Hallazgos Incidentales , Programas Informáticos , Estados UnidosRESUMEN
The originally published version of this Article contained errors in Fig. 2. The numbers below the black arrowheads were incorrect; please see incorrect Figure in associated Correction. These errors have now been corrected in the PDF and HTML versions of the Article.
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PURPOSE: Clinical sequencing emerging in health care may result in secondary findings (SFs). METHODS: Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions. RESULTS: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. CONCLUSION: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.
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Pruebas Genéticas/economía , Hallazgos Incidentales , Secuenciación Completa del Genoma/ética , Adulto , Toma de Decisiones/ética , Revelación , Exoma , Femenino , Pruebas Genéticas/ética , Pruebas Genéticas/normas , Genómica/métodos , Costos de la Atención en Salud , Conocimientos, Actitudes y Práctica en Salud , Personal de Salud , Secuenciación de Nucleótidos de Alto Rendimiento/ética , Humanos , Intención , Masculino , Pacientes , Prevalencia , Secuenciación Completa del Genoma/economíaRESUMEN
PURPOSE: While the diagnostic success of genomic sequencing expands, the complexity of this testing should not be overlooked. Numerous laboratory processes are required to support the identification, interpretation, and reporting of clinically significant variants. This study aimed to examine the workflow and reporting procedures among US laboratories to highlight shared practices and identify areas in need of standardization. METHODS: Surveys and follow-up interviews were conducted with laboratories offering exome and/or genome sequencing to support a research program or for routine clinical services. The 73-item survey elicited multiple choice and free-text responses that were later clarified with phone interviews. RESULTS: Twenty-one laboratories participated. Practices highly concordant across all groups included consent documentation, multiperson case review, and enabling patient opt-out of incidental or secondary findings analysis. Noted divergence included use of phenotypic data to inform case analysis and interpretation and reporting of case-specific quality metrics and methods. Few laboratory policies detailed procedures for data reanalysis, data sharing, or patient access to data. CONCLUSION: This study provides an overview of practices and policies of experienced exome and genome sequencing laboratories. The results enable broader consideration of which practices are becoming standard approaches, where divergence remains, and areas of development in best practice guidelines that may be helpful.Genet Med advance online publication 03 Novemeber 2016.
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Pruebas Genéticas/métodos , Laboratorios/normas , Análisis de Secuencia de ADN/métodos , Revelación , Pruebas Genéticas/normas , Humanos , Hallazgos Incidentales , Difusión de la Información , Laboratorios/ética , Guías de Práctica Clínica como Asunto , Informe de Investigación , Tamaño de la Muestra , Análisis de Secuencia de ADN/normas , Encuestas y CuestionariosRESUMEN
PURPOSE: Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care. METHODS: One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples. Somatic and germ-line alterations were ranked according to therapeutic or clinical relevance. Results were interpreted using an integrated somatic and germ-line framework and returned in accordance with patient preferences. RESULTS: At the time of this analysis, WES had been performed and results returned to the clinical team for 165 participants. Of 768 curated somatic alterations, only 31% were associated with clinical evidence and 69% with preclinical or inferential evidence. Of 806 curated germ-line variants, 5% were clinically relevant and 56% were classified as variants of unknown significance. The variant review and decision-making processes were effective when the process was changed from that of a Molecular Tumor Board to a protocol-based approach. CONCLUSION: The development of novel interpretive and decision-support tools that draw from scientific and clinical evidence will be crucial for the success of cancer precision medicine in WES studies.Genet Med advance online publication 26 January 2017.
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Secuenciación del Exoma/métodos , Exoma/genética , Medicina de Precisión/métodos , Adenocarcinoma/genética , Adenocarcinoma del Pulmón , Adulto , Neoplasias Colorrectales/genética , Bases de Datos Genéticas , Genómica/métodos , Mutación de Línea Germinal/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias Pulmonares/genética , Mutación/genética , Estudios Prospectivos , Análisis de Secuencia de ADN/métodosRESUMEN
This study evaluates µNMR technology for molecular profiling of tumor fine needle aspirates and peripheral blood of melanoma patients. In vitro assessment of melanocyte (MART-1, HMB45) and MAP kinase signaling (pERK, pS6K) molecule expression was performed in human cell lines, while clinical validation was performed in an IRB-approved study of melanoma patients undergoing biopsy and blood sampling. Tumor FNA and blood specimens were compared with BRAF genetic analysis and cross-sectional imaging. µNMR in vitro analysis showed increased expression of melanocyte markers in melanoma cells as well as increased expression of phosphorylated MAP kinase targets in BRAF-mutant melanoma cells. Melanoma patient FNA samples showed increased pERK and pS6K levels in BRAF mutant compared with BRAF WT melanomas, with µNMR blood circulating tumor cell level increased with higher metastatic burden visible on imaging. These results indicate that µNMR technology provides minimally invasive point-of-care evaluation of tumor signaling and metastatic burden in melanoma patients.
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Melanocitos/patología , Melanoma/diagnóstico , Células Neoplásicas Circulantes/patología , Sistemas de Atención de Punto , Transducción de Señal , Biopsia con Aguja Fina/métodos , Línea Celular Tumoral , Humanos , Imagen por Resonancia Magnética/métodos , Melanocitos/metabolismo , Melanoma/sangre , Melanoma/metabolismo , Melanoma/patología , Proteínas Quinasas Activadas por Mitógenos/análisis , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/patología , Proteínas Proto-Oncogénicas B-raf/análisis , Proteínas Proto-Oncogénicas B-raf/metabolismoRESUMEN
Advances in nanotechnology and microfluidics are enabling the analysis of small amounts of human cells. We tested whether recently developed micro-nuclear magnetic resonance (µNMR) technology could be leveraged for diagnosing pulmonary malignancy using fine needle aspirate (FNA) of primary lesions and/or peripheral blood samples. We enrolled a cohort of 35 patients referred for CT biopsy of primary pulmonary nodules, liver or adrenal masses and concurrently obtained FNA and peripheral blood samples. FNA sampling yielded sufficient material for µNMR analysis in 91% of cases and had a sensitivity and specificity of 91.6% and 100% respectively. Interestingly, among blood samples with positive circulating tumor cells (CTC), µNMR analysis of each patient's peripheral blood led to similar diagnosis (malignant vs benign) and differential diagnosis (lung malignancy subtype) in 100% and 90% (18/20) of samples, respectively. µNMR appears to be a valuable, non-invasive adjunct in the diagnosis of lung cancer. FROM THE CLINICAL EDITOR: The authors of this study established that recently developed micro-nuclear magnetic resonance (µNMR) technology can be leveraged for diagnosing pulmonary malignancy using fine needle aspirate (FNA) of primary lesions and/or peripheral blood samples derived from 35 patients, suggesting practical clinical applicability of this technique.
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Compuestos Férricos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Pulmón/patología , Espectroscopía de Resonancia Magnética/instrumentación , Nanopartículas , Células Neoplásicas Circulantes/patología , Adulto , Anciano , Anciano de 80 o más Años , Química Clic , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistemas de Atención de Punto , Adulto JovenRESUMEN
ATM gene is implicated in the development of breast cancer in the heterozygous state, and Ataxia-telangiectasia (A-T) in a homozygous or compound heterozygous state. Ataxia-telangiectasia (A-T) is a rare cerebellar ataxia syndrome presenting with progressive neurologic impairment, telangiectasia, and an increased risk of leukemia and lymphoma. Although the role of ATM, separately, in association with A-T and breast cancer is well documented, there is a limited number of studies investigating ATM variants when segregating with both phenotypes in the same family. Here, using joint analysis and whole genome sequencing, we investigated ATM c.1564_1565del in a family with one homozygous member presenting with A-T (OMIM # 208900) and three heterozygous members, of whom one had breast cancer (OMIM #114480). To our knowledge, this is the first study of ATM c.1564_1565del segregation with both A-T and breast cancer phenotypes within the same kindred. This study highlights the need for a comprehensive genomic approach in the appropriate cancer risk management of heterozygote carriers of ATM in families with A-T.
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Proteínas de la Ataxia Telangiectasia Mutada , Ataxia Telangiectasia , Neoplasias de la Mama , Linaje , Humanos , Ataxia Telangiectasia/genética , Femenino , Neoplasias de la Mama/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Adulto , Masculino , Predisposición Genética a la Enfermedad , Persona de Mediana Edad , Secuenciación Completa del Genoma , HeterocigotoRESUMEN
OBJECTIVE: Turkish genome is underrepresented in large genomic databases. This study aims to evaluate the effect of allele frequency in the Turkish population in determining the clinical utility of germline findings in breast cancer, including invasive lobular carcinoma (ILC), mixed invasive ductal and lobular carcinoma (IDC-L), and ductal carcinoma (DC). METHODS: Two clinic-based cohorts from the Umraniye Research and Training Hospital (URTH) were used in this study: a cohort consisting of 132 women with breast cancer and a non-cancer cohort consisting of 492 participants. The evaluation of the germline landscape was performed by analysis of 27 cancer genes. The frequency and type of variants in the breast cancer cohort were compared to those in the non-cancer cohort to investigate the effect of population genetics. The variant allele frequencies in Turkish Variome and gnomAD were statistically evaluated. RESULTS: The genetic analysis identified 121 variants in the breast cancer cohort (actionable = 32, VUS = 89) and 223 variants in the non-cancer cohort (actionable = 25, VUS = 188). The occurrence of 21 variants in both suggested a possible genetic population effect. Evaluation of allele frequency of 121 variants from the breast cancer cohort showed 22% had a significantly higher value in Turkish Variome compared to gnomAD (p < 0.0001, 95% CI) with a mean difference of 60 times (ranging from 1.37-354.4). After adjusting for variant allele frequency using the ancestry-appropriate database, 6.7% (5/75) of VUS was reclassified to likely benign. CONCLUSION: To our knowledge, this is the first study of population genetic effects in breast cancer subtypes in Turkish women. Our findings underscore the need for a large genomic database representing Turkish population-specific variants. It further highlights the significance of the ancestry-appropriate population database for accurate variant assessment in clinical settings.
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Neoplasias de la Mama , Carcinoma Ductal de Mama , Carcinoma Lobular , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Genómica , OncogenesRESUMEN
BACKGROUND Neurodevelopmental disorders (NDD) are umbrella disorders that encompass global developmental delay (GDD), intellectual disability, autism spectrum disorders, motor developmental disorders, and sleep disorders. Both GDD and autism spectrum disorder are common and yet clinically and genetically heterogeneous disorders. Despite their high prevalence and the advent of sequencing detection methods, the genomic etiology of GDD and autism spectrum disorder in most patients is largely unknown. CASE REPORT In this study, we describe a 6-year-old girl with GDD, autistic features, and structural brain abnormalities, including a moderate reduction in periventricular white matter and bilateral optic nerve hypoplasia, Chiari malformation type I with normal myelinization. A comprehensive joint whole-genome analysis (WGS) of the proband and her unaffected parents was performed. The trio-WGS analysis identified novel de novo nonsense variants AGO3: c.1324C>T (p.Gln442*) and KHSRP: c.1573C>T (p.Gln525*). These variants have not been reported in gnomAD and published literature. AGO3 and KHSRP are not currently associated with a known phenotype in the Online Mendelian Inheritance in Man (OMIM); however, they may be involved in neuronal development. CONCLUSIONS This report highlights the utility of joint WGS analysis in identifying novel de novo genomic alterations in a patient with the spectrum of phenotypes of GDD and neurodevelopmental disorders. The role of these variants and genes in GDD requires further studies.
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Trastorno del Espectro Autista , Discapacidades del Desarrollo , Humanos , Femenino , Niño , Trastorno del Espectro Autista/genética , Discapacidades del Desarrollo/genética , Codón sin Sentido , Secuenciación Completa del GenomaRESUMEN
Women with germline pathogenic variants (PV) in the fumarate hydratase (FH) gene develop cutaneous and uterine leiomyomata and have an increased risk of developing aggressive renal cell carcinomas. Many of these women are unaware of their cancer predisposition until an atypical uterine leiomyoma is diagnosed during a myomectomy or hysterectomy, making a streamlined genetic counseling process after a pathology-based atypical uterine leiomyoma diagnosis critical. However, the prevalence of germline pathogenic/likely PVs in FH among atypical uterine leiomyomata cases is unknown. To better understand FH germline PV prevalence and current patterns of genetic counseling and germline genetic testing, we undertook a retrospective review of atypical uterine leiomyomata cases at a single large center. We compared clinical characteristics between the FH PV, FH wild-type (WT), and unknown genetic testing cohorts. Of the 144 cases with atypical uterine leiomyomata with evaluable clinical data, only 49 (34%) had documented genetic test results, and 12 (8.3%) had a germline FH PV. There were 48 IHC-defined FH-deficient cases, of which 41 (85%) had FH testing and nine had a germline FH PV, representing 22% of the tested cohort and 18.8% of the FH-deficient cohort. Germline FH PVs were present in 8.3% of evaluable patients, representing 24.5% of the cohort that completed genetic testing. These data highlight the disconnect between pathology and genetic counseling, and help to refine risk estimates that can be used when counseling patients with atypical uterine leiomyomata. PREVENTION RELEVANCE: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.
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Fumarato Hidratasa , Pruebas Genéticas , Mutación de Línea Germinal , Leiomioma , Neoplasias Uterinas , Humanos , Femenino , Fumarato Hidratasa/genética , Fumarato Hidratasa/deficiencia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Neoplasias Uterinas/diagnóstico , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Leiomioma/genética , Leiomioma/patología , Leiomioma/diagnóstico , Predisposición Genética a la Enfermedad , Asesoramiento Genético , Leiomiomatosis/genética , Leiomiomatosis/patología , Leiomiomatosis/diagnósticoRESUMEN
PURPOSE: An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS). METHODS: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected. RESULTS: Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15, expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2-15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy. CONCLUSION: This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM#253600) in the same patient. This report highlights the utility of joint analysis and the need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotypes.
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Calpaína , Cromosomas Humanos Par 15 , Síndrome de Prader-Willi , Disomía Uniparental , Humanos , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/patología , Calpaína/genética , Femenino , Cromosomas Humanos Par 15/genética , Disomía Uniparental/genética , Secuenciación Completa del Genoma , Masculino , Proteínas MuscularesRESUMEN
Standard methods of variant assessment in hereditary cancer susceptibility genes are limited by the lack of availability of key supporting evidence. In cancer, information derived from tumors can serve as a useful source in delineating the tumor behavior and the role of germline variants in tumor progression. We have previously demonstrated the value of integrating tumor and germline findings to comprehensively assess germline variants in hereditary cancer syndromes. Building on this work, herein, we present the development and application of the INT2GRATE|HPPGL platform. INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) is a multi-institution oncology consortium that aims to advance the integrated application of constitutional and tumor data and share the integrated variant information in publicly accessible repositories. The INT2GRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma-pheochromocytoma syndromes (HPPGLs). Using INT2GRATE|HPPGL, we analyzed 8600 variants in succinate dehydrogenase (SDHx) genes and their associated clinical evidence. The integrated evidence includes germline variants in SDHx genes; clinical genetics evidence: personal and family history of HPPGL-related tumors; tumor-derived evidence: somatic inactivation of SDHx alleles, KIT and PDGFRA status in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status for SDHA and SDHB genes. After processing, 8600 variants were submitted programmatically from the INT2GRATE|HPPGL platform to ClinVar via a custom-made INT2GRATE|HPPGL variant submission schema and an application programming interface (API). This novel integrated variant assessment and data sharing in hereditary cancers aims to improve the clinical assessment of genomic variants and advance precision oncology.
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Circulating tumor cells (CTC) harvested from peripheral blood have received significant interest as sources for serial sampling to gauge treatment efficacy. Nanotechnology and microfluidic based approaches are emerging to facilitate such analyses. While of considerable clinical importance, there is little information on how similar or different CTCs are from their shedding bulk tumors. In this clinical study, paired tumor fine needle aspirate and peripheral blood samples were obtained from cancer patients during image-guided biopsy. Using targeted magnetic nanoparticles and a point-of-care micro-NMR system, we compared selected biomarkers (EpCAM, EGFR, HER-2 and vimentin) in both CTC and fine needle biopsies of solid epithelial cancers. We show a weak correlation between each paired sample, suggesting that use of CTC as "liquid biopsies" and proxies to metastatic solid lesions could be misleading. FROM THE CLINICAL EDITOR: In this clinical study, paired tumor fine needle aspirate and peripheral blood samples were obtained from patients with solid epithelial cancers during image-guided biopsy. Using targeted magnetic nanoparticles and a point-of-care micro-NMR system, the authors compared selected biomarkers in both circulating tumor cells (CTC) and fine needle biopsies, demonstrating a weak correlation between each paired sample, suggesting that use of CTC could be misleading in this context.
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Biomarcadores de Tumor/metabolismo , Espectroscopía de Resonancia Magnética , Nanopartículas de Magnetita , Miniaturización/instrumentación , Neoplasias/metabolismo , Neoplasias/patología , Células Neoplásicas Circulantes/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/diagnóstico por imagen , Células Neoplásicas Circulantes/patología , RadiografíaRESUMEN
The presence of variants of uncertain significance (VUS) in DNA mismatch repair (MMR) genes leads to uncertainty in the clinical management of patients being evaluated for Lynch syndrome (LS). Currently, there is no platform to systematically use tumor-derived evidence alongside germline data for the assessment of VUS in relation to LS. We developed INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) to leverage information from the tumor genome to inform the potential role of constitutional VUS in MMR genes. INT2GRATE platform has two components: a comprehensive evidence-based decision tree that integrates well-established clinico-genomic data from both the tumor and constitutional genomes to help inform the potential relevance of germline VUS in LS; and a web-based user interface (UI). With the INT2GRATE decision tree operating in the backend, INT2GRATE UI enables the front-end collection of comprehensive clinical genetics and tumor-derived evidence for each VUS to facilitate INT2GRATE assessment and data sharing in the publicly accessible ClinVar database. The performance of the INT2GRATE decision tree was assessed by qualitative retrospective analysis of genomic data from 5057 cancer patients with MMR alterations which included 52 positive control cases. Of 52 positive control cases with LS and pathogenic MMR alterations, 23 had all the testing parameters for the evaluation by INT2GRATE. All these variants were correctly categorized as INT2GRATE POSITIVE. The stringent INT2GRATE decision tree flagged 29 of positive cases by identifying the absence or unusual presentation of specific evidence, highlighting the conservative INT2GRATE logic in favor of a higher degree of confidence in the results. The remaining 99% of cases were correctly categorized as INCONCLUSIVE due to the absence of LS criteria and ≥1 tumor parameters. INT2GRATE is an effective platform for clinical and genetics professionals to collect and assess clinical genetics and complimentary tumor-derived information for each germline VUS in suspected LS patients. Furthermore, INT2GRATE enables the collation of integrated tumor-derived evidence relevant to germline VUS in LS, and sharing them with a large community, a practice that is needed in precision oncology.
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Concurrent pathogenic variants (PVs) in cancer predisposition genes have been reported in 0.1-2% of hereditary cancer (HC) patients. Determining concurrent PVs is crucial for the diagnosis, treatment, and risk assessment of unaffected family members. Next generation sequencing based diagnostic tests, which are widely used in HCs, enable the evaluation of multiple genes in parallel. We have screened the family members of a patient with bilateral breast cancer who was found to have concurrent PVs in BRCA1 (NM_007294.3;c.5102_5103del, p.Leu1701Glnfs*14) and MUTYH (NM_001128425.1;c.884C>T, p.Pro295Leu). Further analysis revealed concurrent PVs in CHEK2 (NM_007194.4;c.1427C>T, p.Thr476Met) and MUTYH (NM_001128425.1;c.884C>T, p.Pro295Leu) in the maternal uncle of the index case. Eight additional family members were found to have PVs in BRCA1 and MUTYH among 26 tested relatives. The sister and the brother of the index case who were diagnosed with breast and colon cancers, respectively, presented with the same genotype as the index case. Each family member was evaluated individually for clinical care and surveillance. This is the first report describing a family with BRCA1, MUTYH and CHEK2 concurrent PVs. Our findings provide valuable information for the assessment and management considerations for families with concurrent PVs.
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Femenino , Humanos , Proteína BRCA1/genética , Neoplasias de la Mama/patología , Quinasa de Punto de Control 2/genética , Familia , Genotipo , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Vulvar melanoma is a rare and aggressive cancer with a poor prognosis. The etiology of mucosal melanoma remains largely uncharacterized and no hereditary risk factors are established for this rare disease. While the germline variant MITF p.E318K confers an increased risk for cutaneous melanoma, this variant has not been associated with risk of non-cutaneous melanoma. Herein, we describe the presence of a germline MITF p.E318K pathogenic variant in a 47-year-old woman with vulvar melanoma and a family history of cutaneous melanoma in a first-degree relative. To our knowledge, this is the first reported case of MITF p.E318K in vulvar melanoma. This finding highlights the potential involvement of MITF p.E318K in risk assessment and clinical management of patients with vulvar melanoma. Further study of this observation is needed to inform appropriate identification of patients with non-cutaneous melanoma for MITF germline genomic evaluation and to potentially guide management for early detection of vulvar melanoma.
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Melanoma , Neoplasias Cutáneas , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Melanoma/genética , Melanoma/patología , Factor de Transcripción Asociado a Microftalmía/genética , Persona de Mediana Edad , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
The interpretation of hereditary genetic sequencing variants is often limited due to the absence of functional data and other key evidence to assess the role of variants in disease. Cancer genetics is unique, as two sets of genomic information are often available from a cancer patient: somatic and germline. Despite the progress made in the integrated analysis of somatic and germline findings, the assessment of pathogenicity of germline variants in high penetrance genes remains grossly underutilized. Indeed, standard ACMG/AMP guidelines for interpreting germline sequence variants do not address the evidence derived from tumor data in cancer. Previously, we have demonstrated the utility of somatic tumor data as supporting evidence to elucidate the role of germline variants in patients suspected with VHL syndrome and other cancers. We have leveraged the key elements of cancer genetics in these cases: genes with expected high disease penetrance and those with a known biallelic mechanism of tumorigenicity. Here we provide our optimized protocol for evaluating the pathogenicity of germline VHL variants using informative somatic profiling data. This protocol provides details of case selection, assessment of personal and family evidence, somatic tumor profiles, and loss of heterozygosity (LOH) as supporting evidence for the re-evaluation of germline variants.
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Genomic profiles of tumors are often unique and represent characteristic mutational signatures defined by DNA damage or DNA repair response processes. The tumor-derived somatic information has been widely used in therapeutic applications, but it is grossly underutilized in the assessment of germline genetic variants. Here, we present a comprehensive approach for evaluating the pathogenicity of germline variants in cancer using an integrated interpretation of somatic and germline genomic data. We have previously demonstrated the utility of this integrated approach in the reassessment of pathogenic germline variants in selected cancer patients with unexpected or non-syndromic phenotypes. The application of this approach is presented in the assessment of rare variants of uncertain significance (VUS) in Lynch-related colon cancer, hereditary paraganglioma-pheochromocytoma syndrome, and Li-Fraumeni syndrome. Using this integrated method, germline VUS in PMS2, MSH6, SDHC, SHDA, and TP53 were assessed in 16 cancer patients after genetic evaluation. Comprehensive clinical criteria, somatic signature profiles, and tumor immunohistochemistry were used to re-classify VUS by upgrading or downgrading the variants to likely or unlikely actionable categories, respectively. Going forward, collation of such germline variants and creation of cross-institutional knowledgebase datasets that include integrated somatic and germline data will be crucial for the assessment of these variants in a larger cancer cohort.