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PURPOSE Whether germline multigene panel testing (MGPT) should be performed in all individuals with colorectal cancer (CRC) remains uncertain. Therefore, we aimed to determine the yield and potential clinical impact of MGPT across a large, diverse CRC cohort. METHODS This was a retrospective cohort study of adults with CRC who underwent MGPT of > 10 genes at a commercial laboratory between March 2015 and May 2021. All data were prospectively collected through a single commercial laboratory and retrospectively analyzed. RESULTS A total of 34,244 individuals with a history of CRC underwent germline MPGT and were included in the analysis. This cohort was predominantly female (60.7%), White (70.6%), and age 50 years or older (68.9%), with 35.5% also reporting a noncolorectal malignancy. At least one pathogenic/likely pathogenic germline variant (PGV) was found in 4,864 (14.2%), with 3,111 (9.1%) having a PGV associated with increased CRC/polyposis risk and 1,048 (3.1%) having an otherwise clinically actionable PGV. Larger gene panels were not clearly associated with higher yield of clinically actionable PGVs. PGVs were more prevalent in individuals of Ashkenazi Jewish descent ( P < .001) and Hispanic ethnicity ( P < .001). Across all ages, panel sizes, and races/ethnicities, the rate of clinically actionable PGVs on MGPT was 7.9% or greater. A variant of uncertain significance was identified in 13,094 individuals (38.2%). Identification of a variant of uncertain significance associated with panel size ( P < .001) and was lower in individuals of Ashkenazi Jewish descent ( P < .001), but higher in Black, Asian, and Hispanic individuals ( P < .001). CONCLUSION To our knowledge, this is the largest study to date examining MGPT in CRC, demonstrating high rates of clinically actionable variants detected across all age groups, panel sizes, and racial/ethnic groups. This work supports consideration of broadening germline genetic testing criteria for individuals with CRC.

10504 Background: Germline genetic testing for patients (pts) with colorectal cancer (CRC) is currently recommended for those diagnosed prior to age 50, as well as other select cases based on personal and/or family history criteria. Whether universal germline multi-gene panel testing (MGPT) should be performed in all pts with CRC remains uncertain given the lack of large-scale studies examining MGPT in CRC across a diverse population. The present study aims to determine the yield, and potential clinical impact, of MGPT across a large CRC cohort. Methods: We conducted a de-identified retrospective cohort study of all pts with CRC who underwent MGPT (excluding patients who underwent testing limited to ≤10 genes) at a commercial laboratory between 03/2015-05/2021. We collected pts demographics from test requisition forms and results of germline MGPT. Clinically actionable PGVs were defined as variants in genes with reported CRC or polyposis risk, as well as other actionable genes associated with clinical management and/or therapeutic implications. Results: A total of 34,210 pts with a history of CRC underwent germline MGPT. These pts were primarily female (60.7%), White (70.6%), and 50 or older (68.8%), with 35.5% reporting an extra-colonic malignancy. Of this cohort, 4,577 (13.4%) were found to carry at least one PGV, with 2,925 (8.6%) having a PGV associated with increased risk of CRC or polyposis. Of all positive pts, 3,038 (66%) had PGVs with precision therapy or clinical trial implications while another 33% had PGVs with published management implications. Among pts under the age of 30 when tested, 23.3% had a clinically actionable PGV compared to 14.7% at age 30-39, 11.7% at 40-49, 12.9% at 50-59, 11.6% at 60-69, 8.9% 70-79, and 7.8% over the age of 80. When compared to pts identified as White, PGVs were more frequently identified in pts of Ashkenazi Jewish descent (p < 0.001) and less frequently identified in those who identified as Hispanic (p < 0.001). VUS was more frequently identified in pts identified as Black, Asian, or Hispanic (p < 0.001). Conclusions: This is the largest study to date examining MGPT in CRC, where we demonstrate high rates of clinically actionable variants across all age groups, self-reported racial/ethnic groups, and panel sizes, with 13% of all CRC pts having a PGV with precision therapy, clinical trial and/or published management implications.This is likely an underestimate as patients with strong clinical suspicion of hereditary CRC (Lynch, FAP) often receive a targeted panel of

e13503Background: Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome caused by mutations in TP53. LFS patients have an increased risk for colorectal cancer (CRC) and surveillance is cur...