Submissions for variant NM_006231.4(POLE):c.4603G>A (p.Gly1535Ser)

gnomAD frequency: 0.00011  dbSNP: rs138564205

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000479918	SCV000289394	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1535 of the POLE protein (p.Gly1535Ser). This variant is present in population databases (rs138564205, gnomAD 0.03%). This missense change has been observed in individual(s) with gastric cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 240530). 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.
GeneDx	RCV000479918	SCV000569841	uncertain significance	not provided	2023-02-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals undergoing multigene panel testing (Mur et al., 2020); This variant is associated with the following publications: (PMID: 32792570)
Counsyl	RCV000232995	SCV000786320	uncertain significance	Colorectal cancer, susceptibility to, 12	2018-04-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765052	SCV000896249	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778818	SCV002015107	likely benign	not specified	2022-11-24	criteria provided, single submitter	clinical testing	Variant summary: POLE c.4603G>A (p.Gly1535Ser) results in a non-conservative amino acid change located in the DNA polymerase epsilon, catalytic subunit A, C-terminal domain (IPR013697) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-05 in 247354 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. c.4603G>A has been reported in the literature in one individual who had personal or familial history of breast cancer (Mur_2020). The report does not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV002258856	SCV002536858	likely benign	Hereditary cancer-predisposing syndrome	2020-11-06	criteria provided, single submitter	curation
Ambry Genetics	RCV002258856	SCV002635457	likely benign	Hereditary cancer-predisposing syndrome	2022-10-28	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.
Fulgent Genetics, Fulgent Genetics	RCV005008196	SCV005633696	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2024-04-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000232995	SCV000493790	uncertain significance	Colorectal cancer, susceptibility to, 12	2016-01-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532929	SCV004738241	likely benign	POLE-related disorder	2024-02-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).