Maegan E. Roberts

Supplementary Materials, References, Tables and Figures

BAP1 Tumor Predisposition Syndrome ( BAP1 ‐TPDS) is caused by germline pathogenic variants in the BAP1 gene and has been associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and other benign cutaneous lesions. Adenomatous colon polyposis has not previously been reported as part of BAP1 ‐TPDS. We report two patients with unexplained adenomatous oligopolyposis and germline BAP1 pathogenic variants. To determine if BAP1 had a role in polypogenesis, we performed somatic mutational analysis on multiple polyps from both patients ( n = 8 total polyps tested). In every polyp tested, we found evidence of second BAP1 allele inactivation, including second somatic BAP1 mutations. Further, we did not detect any mutations in the commonly identified adenomatous polyposis pathway drivers, APC , CTNNB1 , or other WNT/β‐catenin. We did not detect somatic BAP1 mutations in any adenomatous polyps from patients without germline BAP1 pathogenic variants ( n = 151 patients), highlighting the specificity of somatic BAP1 second hit mutations in BAP1 germline carrier polyps. Our findings strongly support that the polyps in these patients were caused by BAP1 , and that adenomatous oligopolyposis is a part of the BAP1 ‐TPDS tumor spectrum. Further work is needed to characterize the penetrance of this new BAP1 ‐associated phenotype.

PURPOSE: The prevalence of pathogenic/likely pathogenic germline variants (PGVs) in gastric cancer (GC) predisposition genes is not well understood. We aimed to determine this in patients with GC undergoing germline genetic testing at a large commercial laboratory. METHODS: This was a cross-sectional study. Retrospective review of genetic testing in patients with GC at a commercial laboratory (Invitae Corp) from March 2015 to July 2023 was performed. Prevalence of PGVs was determined and compared with a control cohort of 20,139 individuals unaffected by cancer. Data were abstracted from test requisition forms. RESULTS: In total, 3,706 patients with GC underwent genetic testing, of which 494 (13.3%) patients carried PGVs, 1,200 (32.4%) had variants of uncertain significance, and 1,890 (51%) had negative testing. PGVs were identified in 38 genes, of which 385 of 494 (77.9%) were in a gene previously associated with GC, including 35% in homologous recombination repair genes ( BRCA1 , BRCA2 , PALB2 , and ATM ), 19.5% in Hereditary Diffuse GC genes ( CDH1 and CTNNA1 ), and 17.4% in Lynch syndrome genes ( MLH1 , MSH2 , MSH6 , PMS2 , and EPCAM ). Comparing the GC cohort with the unaffected cohort, it was found that there was significant enrichment of PGVs in most GC-associated genes, except for APC , EPCAM , MUTYH , and PMS2 . Odds of carrying a PGV was increased significantly in males and patients with a personal history of another cancer with odds ratio (OR) of 1.3 (95% CI, 1.1 to 1.6) and OR, 1.4 (95% CI, 1.1 to 1.7), respectively. CONCLUSION: In this large study of genetic testing in patients with GC, more than one in eight patients referred for germline testing was found to harbor a PGV in a cancer predisposition gene, which is higher than previous estimates. Most PGVs were identified in genes previously associated with GC.

Supplementary Materials, References, Tables and Figures

Supplementary Materials, References, Tables and Figures

Supplementary Materials, References, Tables and Figures

Supplementary Materials, References, Tables and Figures

Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C−/− cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. Significance: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.

POLE is a pleiotropic gene with phenotypic expression of pathogenic variants depending on the type of variant, impact on the protein, and mode of inheritance. Heterozygous missense variants located within the exonuclease domain have been shown to result in polymerase proofreading‐associated polyposis (PPAP) which is characterized by an increased risk for colon polyps and colorectal cancer. Biallelic variants resulting in markedly reduced amounts of normal protein have been reported in two separate recessive pediatric syndromes: facial dysmorphism, immunodeficiency, livedo, and short stature as well as intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genital anomalies. Here we report two siblings identified to have POLE c.1686 + 32C > G in trans with POLE p.(Glu709*) via exome sequencing. A detailed review of the reported phenotypes in these two siblings and from available literature revealed that individuals with biallelic POLE pathogenic variants resulting in partial loss‐of‐function present with a similar phenotype: short stature and facial dysmorphism with or without immunodeficiency. These data suggest a phenotypic continuum between the previously reported POLE‐related recessive disorders.

Clinical guidelines recommend universal tumor screening (UTS) of colorectal and endometrial cancers for Lynch syndrome (LS). There are limited guidelines for how to integrate germline testing and somatic tumor testing after a mismatch repair deficient (dMMR) tumor is identified. We sought to characterize current practice patterns and barriers to preferred practice among clinical providers in high‐risk cancer programs. A clinical practice survey was sent to 423 active members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA‐IGC) with a follow‐up survey sent to 103 clinician responders. The survey outlined clinical vignettes and asked respondents their preferred next test. The survey intended to assess: (1) the role of patient age and family history in risk assessment and (2) barriers to preferred genetic testing. Genetic test options included targeted germline testing based on dMMR expression, germline testing for LS, germline testing with a multigene cancer panel including LS, or paired tumor/germline testing including LS. In October 2020, 117 of 423 (28%) members completed the initial survey including 103 (88%) currently active clinicians. In April 2021, a follow‐up survey was sent to active clinicians, with 45 (44%) completing this second survey. After selecting their preferred next germline or paired tumor/germline tumor test based on the clinical vignette, 39% of respondents reported wanting to make a different choice for the initial genetic test without any testing barriers. The proportion of respondents choosing a different initial genetic test was dependent on the proband's age at diagnosis and specified family history. The reported barriers included patient's lack of insurance coverage, patient unable/unwilling to self‐pay for proposed testing, and inadequate tumor tissue. Responders reported insurance, financial constraints, and limited tumor tissue as influencing preferred genetic testing in high‐risk clinics, thus resulting in possible under‐diagnosis of LS and impacting potential surveillance and cascade testing of at‐risk relatives.