Submissions for variant NM_006231.4(POLE):c.940T>G (p.Ser314Ala)

gnomAD frequency: 0.00011  dbSNP: rs770403791

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210168	SCV000266225	uncertain significance	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657078	SCV000544122	likely benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000657078	SCV000568365	likely benign	not provided	2019-10-17	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31866764, 24410847, 26845104, 27720647, 32567205)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483379	SCV000602106	benign	not specified	2021-07-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210168	SCV000671262	likely benign	Hereditary cancer-predisposing syndrome	2024-08-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000474943	SCV000784851	uncertain significance	Colorectal cancer, susceptibility to, 12	2017-01-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000709278	SCV000838709	uncertain significance	Familial colorectal cancer	2018-07-02	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000474943	SCV001737422	uncertain significance	Colorectal cancer, susceptibility to, 12	2021-04-22	criteria provided, single submitter	clinical testing	The POLE c.940T>G (p.Ser314Ala) missense change has a maximum non-founder population frequency of 0.0016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-133252760-A-C?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in an individual with early-onset colorectal cancer and a strong family history of colorectal cancer and familial adenomatous polyposis (PMID: 32567205) and an individual with endometrial carcinoma (PMID: 31866764). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Sema4, Sema4	RCV000210168	SCV002536956	likely benign	Hereditary cancer-predisposing syndrome	2021-02-13	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000474943	SCV004018515	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-04-19	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV004541300	SCV004787114	uncertain significance	POLE-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The POLE c.940T>G variant is predicted to result in the amino acid substitution p.Ser314Ala. This variant was reported in an individual with endometrial carcinoma (Siraj et al 2019. PubMed ID: 31866764) and in another individual with a personal history of early onset colorectal cancer and significant family history of colorectal cancer/familial adenomatous polyposis (Fig 1 in Siraj AK et al 2020. PubMed ID: 32567205). This variant is reported in 0.23% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is reported with conflicting interpretations of benign to variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/224589/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.