Submissions for variant NM_006231.4(POLE):c.6050G>A (p.Arg2017His)

gnomAD frequency: 0.00011  dbSNP: rs144178150

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000985988	SCV000289446	uncertain significance	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2017 of the POLE protein (p.Arg2017His). This variant is present in population databases (rs144178150, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 240582). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000765045	SCV000896242	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985988	SCV001134745	uncertain significance	not provided	2020-03-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000985988	SCV001818092	uncertain significance	not provided	2024-12-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28427513)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307464	SCV002600445	uncertain significance	not specified	2022-10-11	criteria provided, single submitter	clinical testing	Variant summary: POLE c.6050G>A (p.Arg2017His) results in a non-conservative amino acid change in the encoded protein sequence. Three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 248196 control chromosomes, predominantly at a frequency of 6.2e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6050G>A has been reported in the literature in individuals affected with Breast Cancer without strong evidence for causality (Zhao_2019). This report does not provide unequivocal conclusions about association of the variant with Colorectal Cancer. Co-occurrence with a pathogenic variant has been reported (CHEK2 c.1100del, p.T367MfsX15), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
Ambry Genetics	RCV004943814	SCV005481520	likely benign	Hereditary cancer-predisposing syndrome	2024-12-05	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.