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46 Background: Genetic susceptibility to colorectal cancer (CRC) include well-defined hereditary syndromes such as Lynch Syndrome, Familial Adenomatous Polyposis syndrome (FAP), MUTYH-Associated Polyposis syndrome (MAP) and other less common syndromes. National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals meeting certain criteria have detailed risk assessment and potential genetic testing. Here, we describe the clinical and molecular characteristics of patients with personal history of CRC evaluated by cancer genetics counseling services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of CRC were identified (N = 52) and their clinical and molecular characteristics were summarized. Results: The median age is 50 years-old (29-82). Thirty-five (67%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 75%, 19% and 6% respectively. The primary tumor location was in the right colon, left colon and rectum in 29%, 37% and 27% of our cohort respectively. In 7%, the primary location of the tumor was not available. In our cohort, 11 out of 52 (21%) patients had a pathogenic germline mutation and 9 patients (17%) had a germline variant of unknown significance (VUS). Among patients with pathogenic germline mutations (N = 11), 4 patients had MSH2 mutations (MSH2 c.1759+1G > A, MSH2 c. 1687dupT, MSH2 c.1861C > T and MSH2 c.811_814delTCTG), 1 patient had a MSH6 mutation (MSH6 c.1012A > T), 1 patient had a PMS2 mutation (PMS2 c.2182_2184delACTinsG), 3 patients had CHEK2 mutations (CHEK2 c.1100delC and CHEK2 c.470T > C (p.I157T)), 2 patients had MUTYH mutations (MUTYH c.1187G > A and MUTYH c.536A > G) and 1 patient had a BRCA2 mutation (BRCA2 c.2808_2811delACAA). One patient had a CHEK2 and a MUTYH mutation. The VUS mutations in our cohort were POLE c.1645T > C, POLE c.5480C > T, c.2999G > A, MLH1 c.1628A > G, CTNNA1 c.503G > A, MSH2 c.128A > G, NBN c.16C > T, ATM c.6537T > G and AXIN2, BRCA1, NTHL1 mutations. Conclusions: In our cohort of patients with personal history of CRC, the majority of patients (62%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 21% and 17% of the patients respectively. Lynch Syndrome was the most commonly diagnosed hereditary CRC syndrome with 6 out of 11 patients found to have MMR germline mutations. Other pathogenic mutations were identified in the CHEK2, MUTYH and BRCA2 genes.

47 Background: National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals with >10 adenomatous polyps, ≥2 hamartomatous polyps, or ≥5 serrated polyps proximal to the sigmoid colon have detailed risk assessment and potential genetic testing to rule out polyposis syndrome. Here, we describe germline testing of patients with a personal history of colorectal polyposis by Cancer Genetics Counseling Services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of colorectal polyposis were identified (N=20) and their germline testing results were summarized. Results: The reasons for referral to the Cancer Genetics Counseling Services were personal history of >10 adenomatous polyps (N=13), personal and family history of colorectal polyposis (N=3), personal history of juvenile colorectal polyps (N=3) or personal history of ≥2 hamartomatous polyps (N=1). The median age is 58 years-old (1-84). Ten (50%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 80%, 10% and 10% respectively. In our cohort, 6 out of 20 (30%) patients had a pathogenic germline mutation, 5 (25%) patients had variant of unknown significance (VUS) and 9 (45%) patients had negative testing. Among patients with pathogenic germline mutations, 3 patients had a pathogenic APC mutation (APC c.1659G>A, APC c.2802C>A and APC c.1643dupT) and were diagnosed with Familial Adenomatous Polyposis (FAP). One patient had 2 pathogenic MUTYH mutations (MUTYH c.536A>G and MUTYH c.1187G>A) and was diagnosed with One patient had a pathogenic PTEN c.634+5G>A mutation and was diagnosed with PTEN Hamartoma Tumor Syndrome. Among the 3 patients with a personal history of juvenile colorectal polyps, one patient had a CHEK2 c.190G>A mutation while the other two had negative genetic test results. The VUS mutations in our cohort were MRE11A c.826C>T, BLM c.3478T>C, BRCA2 c.2519T>C, CHEK2 p.V395L and CTNNA1 c.392dupT. Conclusions: In our cohort of patients with personal history of colorectal polyposis, the majority of patients (45%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 30% and 25% of the patients, respectively. FAP Syndrome was the most commonly diagnosed hereditary polyposis syndrome with 3 patients found to have APC germline mutations. Other pathogenic mutations were identified in the MUTYH, PTEN and CHEK2 genes. Patients with MUTYH and PTEN mutations were diagnosed with MAP and PTEN Hamartoma Tumor Syndromes respectively.

44 Background: Checkpoint Kinase 2 (CHEK 2) encodes the protein CHK2, a serine/threonine kinase involved in pathways that conduct DNA repair as well as apoptosis in response to initial DNA damage. Germline mutations in the CHEK2 gene are associated with several malignancies such as colon, breast, stomach, prostate, kidney, thyroid and soft tissue cancers. Here, we describe the clinical and molecular characteristics of patients with personal or family history of gastrointestinal (GI) malignancies/polyposis and CHEK2 gene mutations. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a germline CHEK2 mutation were identified (N = 16). Patients with a CHEK2 mutation and personal and family history of GI malignancies/polyposis were further explored and their clinical and molecualr characteristics are summarized. Results: The reasons for referral to the Cancer Genetics Counseling Services in patients with pathogenic CHEK2 mutations were personal history of colon cancer (N = 3) and family history of colon cancer (N = 4). One patient with the CHEK2 c.1100delC mutation had a personal history of juvenile polyposis syndrome and a family history of colon cancer. In our cohort, 11 out of 16 (69%) patients had a CHEK2 mutation and personal or family history of GI malignancies/polyposis. The median age was 57 years old (25-80). Six (55%) patients were males. All (100%) patients were Caucasians. Seven (64%) patients had a pathogenic germline CHEK2 mutation and 4 (36%) patients had a variant of unknown significance (VUS). Among patients with pathogenic germline CHEK2 mutations (N = 7), 5 (72%) patients had CHEK2 c.1100delC mutation, 1 (14%) patient had CHEK2 c.190G > A mutation and 1 (14%) patient had CHEK2 c.470T > C mutation. The CHEK2 VUS mutations seen in our cohort were CHEK2 c.539G > A, CHEK2 p.V395L, CHEK2 gain of exons 3-15 and CHEK2 c.1421G > A mutations. Conclusions: All patients in our cohort with CHEK2 mutations were Caucasians. The majority of our patients (69%) had an underlying personal or family history of GI malignancies/polyposis. In patients with personal or family history of GI malignancies/polyposis and CHEK2 mutation, 64% were found to have pathogenic CHEK2 mutations. The most common diagnosed CHEK2 mutation in our cohort was CHEK2 c.1100delC mutation.