Submissions for variant NM_006231.4(POLE):c.5333C>T (p.Ala1778Val)

dbSNP: rs2138523727

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002016430	SCV002303054	uncertain significance	Colorectal cancer, susceptibility to, 12	2022-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1778 of the POLE protein (p.Ala1778Val). This variant is not present in population databases (gnomAD no frequency). 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: 1508880). 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. 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.
PreventionGenetics, part of Exact Sciences	RCV004538734	SCV004720477	uncertain significance	POLE-related disorder	2023-12-28	no assertion criteria provided	clinical testing	The POLE c.5333C>T variant is predicted to result in the amino acid substitution p.Ala1778Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is listed in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/1508880/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.