What Is a Variant of Uncertain Significance in Genetic Testing?

Genetic testing is a critical tool in the medical management of disease; however, for variants of uncertain significance there is insufficient evidence to prove a connection between the variant and disease and they should not be used as a basis for clinical decisions.

Inherited TP53 Variants and Risk of Prostate Cancer.

BACKGROUND: Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53. OBJECTIVE: To determine whether gTP53 predisposes to prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer. RESULTS AND LIMITATIONS: We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis. CONCLUSIONS: Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing. PATIENT SUMMARY: Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.

Inherited DNA-repair gene mutations in African American men with prostate cancer.

African American men with prostate cancer are understudied relative to Caucasians with prostate cancer with regard to testing for pathogenic germline DNA repair gene mutations. Herein we evaluate these two populations in a large commercial dataset and compare the detection of pathogenic/likely pathogenic alterations in 14 well annotated DNA repair genes (BRCA2, BRCA1, PALB2, ATM, RAD51C, CHEK2, PMS2, BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, and RAD51D). Overall, pathogenic or likely pathogenic alterations in these 14 DNA repair genes were less likely to be detected in African Americans as compared to Caucasians. Upon a more in-depth analysis, the risk of germline pathogenic/likely pathogenic BRCA mutations was similar between the two populations whereas there was a lower risk among African Americans for the non-BRCA mutations. No African American men were noted to have mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, and RAD51D in this data set. Stage, grade, and metastatic status were not assessed in this group of patients. Larger and more detailed studies conducted in men with prostate cancer are required to confirm these findings.

Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines.

IMPORTANCE: Prostate cancer is the third leading cause of cancer-related death in men in the United States. Although serious, most of these diagnoses are not terminal. Inherited risk for prostate cancer is associated with aggressive disease and poorer outcomes, indicating a critical need for increased genetic screening to identify disease-causing variants that can pinpoint individuals at increased risk for metastatic castration-resistant prostate cancer. OBJECTIVE: To identify positive (pathogenic, likely pathogenic, and increased risk) germline variants in a large prostate cancer cohort and to evaluate the usefulness of current practice guidelines in recognizing individuals at increased risk for prostate cancer who would benefit from diagnostic genetic testing. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of data from 3607 men with a personal history of prostate cancer who underwent germline genetic testing between 2013 and 2018 and were unselected for family history, stage of disease, or age at diagnosis. Referral-based testing was performed at a Clinical Laboratory Improvement Amendments/College of American Pathologists-certified diagnostic laboratory. All analysis took place between February 2017 and August 2018. MAIN OUTCOMES AND MEASURES: The frequency and distribution of positive germline variants, and the percentage of individuals with prostate cancer who met National Comprehensive Cancer Network (NCCN) guidelines for germline genetic testing. RESULTS: Of 3607 men (mean [SD] age at testing, 67 [9.51] years; mean age at diagnosis, 60 [9.05] years) with a personal diagnosis of prostate cancer who were referred for genetic testing, 620 (17.2%) had positive germline variants, of which only 30.7% were variants in BRCA1/2. Positive variants in HOXB13, a gene associated only with prostate cancer risk, were identified in 30 patients (4.5%). DNA mismatch repair variants with substantial known therapeutic implications were detected in 1.74% of variants in the total population tested. Examination of self-reported family histories indicated that 229 individuals (37%) with positive variants in this cohort would not have been approved for genetic testing using the NCCN genetic/familial breast and ovarian guidelines for patients with prostate cancer. CONCLUSIONS AND RELEVANCE: Current NCCN guidelines and Gleason scores cannot reliably stratify patients with prostate cancer for the presence or absence of pathogenic germline variants. Most positive genetic test results identified in this study have important management implications for patients and their families, which underscores the need to revisit current guidelines.