Fibroblast testing can inform medical management in individuals with mosaic variants detected on hereditary cancer panels.

Mosaic variants are regularly detected on hereditary cancer genetic tests. While some of these variants may be constitutional, the majority are likely limited to blood lineages. In the present study, we correlate clinical histories from individuals with mosaic findings identified on hereditary cancer testing and the outcomes of follow-up fibroblast (FB) testing. We observed 620 mosaic variants, including 339 pathogenic or likely pathogenic variants (PVs) occurring most often in TP53, CHEK2, ATM, and NF1. About half of individuals with NF1 mosaic PVs did not report any clinical features of NF1 and were older at testing (p<0.0001) compared to those with an NF1-related phenotype. Among 42 mosaic PVs evaluated by FB testing, 17 (40.5%) were confirmed in FB and were mostly identified in individuals with phenotypes consistent with the gene disease spectrum. Our data show that FB testing is helpful for identifying those with likely constitutional mosaicism benefitting from increased screening and follow-up vs. those with blood-limited variants potentially not requiring intense surveillance but warranting further hematologic work-up.

Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer.

We aimed to determine whether monoallelic MUTYH pathogenic and likely pathogenic variants (PVs) are associated with colorectal, breast, and endometrial cancer. Cases were individuals with colorectal, female breast, or endometrial cancer who reported European ancestry alone and underwent a multi-gene hereditary cancer panel at a large reference laboratory. Controls were individuals of European (non-Finnish) descent from GnomAD with cancer cohorts removed. We performed a Fisher's exact test to generate odds ratios (ORs) with 95% confidence intervals (CI). Prevalence of single MUTYH PVs in cancer cohorts versus controls, respectively, was: colorectal cancer, 2.1% vs. 1.8% (OR 1.2, 95% CI 0.99-1.5, p = 0.064); breast cancer 1.9% vs. 1.7% (OR 1.1, 95% CI 0.96-1.3, p = 0.15); and endometrial cancer, 1.7% vs. 1.7% (OR 0.98; 95% CI 0.70-1.3, p = 0.94). Using the largest colorectal and endometrial cancer cohorts and one of the largest breast cancer cohorts from a single case-control study, we did not observe a significant difference in the prevalence of monoallelic MUTYH PVs in these cohorts compared to controls. Additionally, frequencies among cancer cohorts were consistent with the published MUTYH carrier frequency of 1-2%. These findings suggest there is no association between colorectal, endometrial, or breast cancer and MUTYH heterozygosity in individuals of European ancestry.

Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing.

PURPOSE: Although CHEK2 is a well-established cancer gene, questions remain including whether risks vary substantially between different variants and whether biallelic carriers have higher risks than heterozygotes. We report on a cohort of individuals with CHEK2 pathogenic and likely pathogenic variants (collectively, PV) in order to better characterize this gene. METHODS: We retrospectively queried samples submitted for multi-gene hereditary cancer testing to identify individuals with CHEK2 PVs and assessed differences in phenotypes among various genotypes. RESULTS: CHEK2 PVs were identified in 2508 individuals, including 32 individuals with biallelic CHEK2 PVs. Breast (female, 59.9% and male, 11.8%), prostate (20.1%), and colorectal (3.5%), were among the most frequently reported cancers. Select missense PVs showed similar cancer prevalence to truncating PVs while some others showed lower prevalence. No significant differences were observed between biallelic carriers and heterozygotes. CONCLUSIONS: Our data support that some, but not all, CHEK2 missense PVs demonstrate lower cancer prevalence; further studies are needed to continue characterizing possible variant specific risks. In addition, biallelic CHEK2 PVs do not appear to be associated with a more severe phenotype than single CHEK2 PVs. Furthermore, co-occurrences with PVs in other cancer risk genes are common among CHEK2 heterozygotes and often warrant additional management.

Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis.

Biallelic pathogenic variants (PVs) in MUTYH cause MUTYH-Associated Polyposis (MAP), which displays phenotypic overlap with other hereditary colorectal cancer (CRC) syndromes including Familial Adenomatous Polyposis (FAP) and Lynch syndrome. We report the phenotypic spectrum of MAP in the context of multi-gene hereditary cancer panel testing. Genetic testing results and clinical histories were reviewed for individuals with biallelic MUTYH PVs detected by panel testing at a single commercial molecular diagnostic laboratory. Biallelic MUTYH PVs were identified in 82 individuals (representing 0.2% of tested individuals) with most (75/82; 91.5%) reporting a personal history of CRC and/or polyps. Ten percent (6/61) of individuals reporting polyp number reported fewer than 10 polyps and therefore did not meet current MAP testing criteria. Extracolonic cancers (21/82; 25.6%), multiple primaries (19/82; 23.2%), Lynch-like (17/82; 20.7%) and FAP-like phenotypes (16/82; 19.5%) were observed, including individuals with mismatch repair-deficient tumors (3/82; 3.7%), sebaceous neoplasms (2/82; 2.4%), or congenital hypertrophy of the retinal pigment epithelium (CHRPE) (2/82; 2.4%). We report what is to our knowledge the first cohort of individuals with MAP identified by panel testing. The phenotypic spectrum of MAP observed in this cohort aligns with the published literature. In addition to standard indications for MUTYH testing, our data provide evidence to support consideration of MAP in the differential diagnosis for some individuals with fewer than 10 polyps, depending on other personal and/or family history, as well as for individuals suspected to have Lynch syndrome or FAP.