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PURPOSE PTEN-associated clinical syndromes such as Cowden syndrome (CS) increase cancer risk and have historically been diagnosed based upon phenotypic criteria. Because not all patients clinically diagnosed with CS have PTEN pathogenic variants (PVs), and not all patients with PTEN PVs have been clinically diagnosed with CS, the cancer risk conferred by PTEN PVs calculated from cohorts of patients with clinical diagnoses of CS/CS-like phenotypes may be inaccurate. METHODS We assessed a consecutive cohort of 727,091 individuals tested clinically for hereditary cancer risk, with a multigene panel between September 2013 and February 2022. Multivariable logistic regression models accounting for personal and family cancer history, age, sex, and ancestry were used to quantify disease risks associated with PTEN PVs. RESULTS PTEN PVs were detected in 0.027% (193/727,091) of the study population, and were associated with a high risk of female breast cancer (odds ratio [OR], 7.88; 95% CI, 5.57 to 11.16; P = 2.3 × 10−31), endometrial cancer (OR, 13.51; 95% CI, 8.77 to 20.83; P = 4.2 × 10−32), thyroid cancer (OR, 4.88; 95% CI, 2.64 to 9.01; P = 4.0 × 10−7), and colon polyposis (OR, 31.60; CI, 15.60 to 64.02; P = 9.0 × 10−22). We observed modest evidence suggesting that PTEN PVs may be associated with ovarian cancer risk (OR, 3.77; 95% CI, 1.71 to 8.32; P = 9.9 × 10−4). Among patients with similar personal/family history and ancestry, every 5-year increase in age of diagnosis decreased the likelihood of detecting a PTEN PV by roughly 60%. CONCLUSION We demonstrate that PTEN PVs are associated with significantly increased risk for a range of cancers. Together with the observation that PTEN PV carriers had earlier disease onset relative to otherwise comparable noncarriers, our results may guide screening protocols, inform risk-management strategies, and warrant enhanced surveillance approaches that improve clinical outcomes for PTEN PV carriers, regardless of their clinical presentation.

Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel (N = 627,742). Cancer risks for ATM PV carriers (N = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24–5.47), prostate (OR, 2.58; 95% CI, 1.93–3.44), gastric (OR, 2.97; 95% CI, 1.66–5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89–2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76–5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR, 1.80; 95% CI, 1.61–2.02), male breast cancer (OR, 1.72; 95% CI, 1.08–2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35–1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24–1.79), and melanoma (OR, 1.46; 95% CI, 1.18–1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection. Prevention Relevance: This study estimated risks for multiple cancers associated with ATM pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants.

Expanded genetic test utilization to guide cancer management has driven the development of larger gene panels and greater diversity in the patient population pursuing testing, resulting in increased identification of atypical or technically challenging genetic findings. To ensure appropriate patient care, it is critical that genetic tests adequately identify and characterize these findings. We describe genetic testing challenges frequently encountered by our laboratory and the methodologies we employ to improve test accuracy for the identification and characterization of atypical genetic findings. While these findings may be individually rare, 15,745 (9%) individuals tested by our laboratory for hereditary cancer risk had an atypical genetic finding, highlighting the importance of employing highly accurate and comprehensive methods in clinical genetic testing.

Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability [MSI], mismatch repair [MMR] deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results. All participants underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene. Results One hundred five (9.9%; 95% CI, 8.2% to 11.9%) of 1,058 participants carried one or more pathogenic mutations, including 33 (3.1%) with Lynch syndrome (LS). Twenty-eight (96.6%) of 29 available LS CRCs demonstrated abnormal MSI/MMR results. Seventy-four (7.0%) of 1,058 participants carried non-LS gene mutations, including 23 (2.2%) with mutations in high-penetrance genes (five APC, three biallelic MUTYH, 11 BRCA1/2, two PALB2, one CDKN2A, and one TP53), 15 of whom lacked clinical histories suggestive of their underlying mutation. Thirty-eight (3.6%) participants had moderate-penetrance CRC risk gene mutations (19 monoallelic MUTYH, 17 APC*I1307K, two CHEK2). Neither proband age at CRC diagnosis, family history of CRC, nor personal history of other cancers significantly predicted the presence of pathogenic mutations in non-LS genes. Conclusion Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC. MSI/MMR testing reliably identifies LS probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.

Background: Germ-line pathogenic variants (PV) in ATM are often considered low-to-moderate penetrance risk factors for breast cancer (BC), conferring a two-fold increased BC risk among heterozygous PV carriers. Several other cancers have been associated with ATM PV such as melanoma, thyroid cancer, prostate cancer, pancreatic cancer, gastro-esophageal cancers, colorectal cancer, and ovarian cancer. Estimating the diverse cancer risks attributable to ATM PVs may present challenges due to the low-to-moderate penetrance of ATM PV for some cancers, requiring large samples of tested patients to estimate risk with precision, and the potential for substantial variability in penetrance of particular ATM PV such as the c.7271T>G PV reported by previous studies. We investigated cancer risks with ATM PV in a large clinical testing dataset. Methods: Results of 614,344 individuals undergoing clinical analysis of ATM as part of a multi-gene hereditary cancer gene panel between 09/2013 and 06/2019 were reviewed. Patient age, sex, ancestry, personal and family cancer history were extracted from a test requisition form. PV included variants classified as suspected deleterious or deleterious (hereafter referred to as pathogenic). Risk estimates are estimated using multivariate logistic regression and are reported as odds ratios (OR) with 95% confidence intervals (CI). Results: PV in ATM were identified in 4,372/614,344 (0.7%) individuals: 4,155/592,881 (0.7%) females and 217/21,463 (1.0%) males. 1,603/4,155 (38.6%) of female ATM PV carriers had invasive BC or DCIS. Overall, ATM PV were associated with a 2-fold increased risk for invasive BC [OR 2.01, 95% CI 1.86-2.16] and DCIS [OR 1.82, 95% CI 1.62-2.04]. A prevalent missense PV c.7271T>G, predicted to lead to inactivation of ATM kinase activity and that has previously been described as high penetrance (Goldgar DE et al, Breast Cancer Res 2011), represented 5.1% (n=223) of all ATM PV, and was associated with a particularly high risk of invasive BC [OR 3.80, 95% CI 2.78-5.19] but no increased risk of DCIS. Significantly elevated risks of pancreatic cancer, gastric cancer, prostate cancer, ovarian cancer, colon cancer and melanoma were also observed among ATM PV carriers (see Table 1). Median age of invasive BC diagnosis was similar in carriers and non-carriers of ATM PV. Conclusions: ATM PV are associated with 1.5-fold to >4-fold increased cancer risks across a variety of disease sites, including invasive BC (2-fold increased risk). Cancer risks also demonstrate mutation-specific variability, as suggested by the 4-fold increased risk of invasive BC in carriers of the ATM PV c.7271T>G. Larger and/or pooled studies are critical to further refine the breadth and magnitude of ATM-associated cancer risk and to improve clinical management guidelines for ATM PV carriers. Table 1: Odds ratios for cancer risks in c.7271T>G and all other ATM PV carriersAll ATM PVs (excluding c.7271T>G)c.7271T>GCancer OR (95% CI)p-valueOR (95% CI)p-valueBreast, Invasive1.94 (1.79, 2.09) Citation Format: Michael J Hall, Katie Larson, Ryan Bernhisel, Elisha Hughes, Eric Rosenthal, Nanda Singh, Johnathan M Lancaster, Allison W Kurian. Cancer risks associated with pathogenic variants in the ataxia telangiectasia mutated (ATM) gene [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-02.

Background Panel-based genetic testing has identified increasing numbers of patients with pancreatic ductal adenocarcinoma (PDAC) who carry germline mutations. However, small sample sizes or number of genes evaluated limit prevalence estimates of these mutations. We estimated prevalence of mutations in PDAC patients with positive family history. Methods We sequenced 25 cancer susceptibility genes in lymphocyte DNA from 302 PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreatic Research Registry. Kindreds containing at least two first-degree relatives with PDAC met criteria for Familial Pancreatic Cancer (FPC), while the remaining were familial, but not FPC. Results Thirty-six patients (12%) carried at least one deleterious mutation in one of 11 genes. Of FPC patients, 25/185 (14%) were carriers, while 11/117 (9%) non-FPC patients with family history were carriers. Deleterious mutations (n) identified in PDAC patients were BRCA2 (11), ATM (8), CDKN2A (4), CHEK2 (4), MUTYH/MYH (3 heterozygotes, not biallelic), BRCA1 (2), and 1 each in BARD1, MSH2, NBN, PALB2, and PMS2. Novel mutations were found in ATM, BARD1, and PMS2. Conclusions Multiple susceptibility gene testing in PDAC patients with family history of pancreatic cancer is warranted regardless of FPC status, and will inform genetic risk counseling for families.

Purpose Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. Methods Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. Results Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Conclusion Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.

1501Background: Microsatellite instability (MSI) and mismatch repair protein immunohistochemistry (MMR IHC) are standard of care to screen for the 3% of CRCs that arise due to Lynch syndrome (LS). ...

4108Background: Availability of cancer gene mutation panel-based screening will identify increasing numbers of patients who carry diverse germline mutations. Prevalence of mutations and survival by...

1503 Background: Evaluation of women with triple negative BC for germline BRCA1/2 mutations has become standard of care due to its impact on management and 11% mutation prevalence. Approximately 70...

1533 Background: Endometrial carcinoma (EC) is associated with multiple hereditary cancer genes including Lynch syndrome (LS) genes, which are estimated to account for 2-6% of all cases. The role o...