Submissions for variant NM_002691.4(POLD1):c.1174G>A (p.Val392Met)

gnomAD frequency: 0.00002  dbSNP: rs778843530

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472244	SCV000547605	uncertain significance	Colorectal cancer, susceptibility to, 10	2025-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 392 of the POLD1 protein (p.Val392Met). This variant is present in population databases (rs778843530, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 408053). 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 POLD1 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.
Ambry Genetics	RCV001010133	SCV001170284	likely benign	Hereditary cancer-predisposing syndrome	2024-08-13	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.
GeneDx	RCV001764404	SCV001999597	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a cohort of individuals with hypertriglyceridemia and familial hypercholesterolemia (Dron et al., 2020); This variant is associated with the following publications: (PMID: 23528559, 29717118, 32041611, 20951805)
Genetic Services Laboratory, University of Chicago	RCV001821259	SCV002065989	uncertain significance	not specified	2021-09-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000472244	SCV004203502	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-03-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001764404	SCV004219051	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	The POLD1 c.1174G>A (p.Val392Met) variant has been reported in individuals with endometrial cancer as a somatic variant (PMID: 23528559 (2013), 29717118 (2018)). It has also been reported in a cohort of individuals with dyslipidemia and metabolic disorders (PMID: 32041611 (2020)). The frequency of this variant in the general population, 0.000035 (4/113762 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.