Submissions for variant NM_006231.4(POLE):c.350C>T (p.Ser117Leu)

gnomAD frequency: 0.00002  dbSNP: rs372057971

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002286825	SCV001395862	uncertain significance	not provided	2023-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 117 of the POLE protein (p.Ser117Leu). This variant is present in population databases (rs372057971, 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: 951725). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLE protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV002286825	SCV002576893	uncertain significance	not provided	2022-03-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001223703	SCV004031220	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-07-06	criteria provided, single submitter	clinical testing	The POLE c.350C>T (p.Ser117Leu) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in 1 of 829 serous ovarian cancer cases and 0 of 913 controls (PMID: 32546565). To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003398967	SCV004104215	uncertain significance	POLE-related condition	2023-02-20	criteria provided, single submitter	clinical testing	The POLE c.350C>T variant is predicted to result in the amino acid substitution p.Ser117Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133256613-G-A). In ClinVar, this variant is interpreted as uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/951725/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.