Submissions for variant NM_002691.4(POLD1):c.1696G>A (p.Glu566Lys)

gnomAD frequency: 0.00006  dbSNP: rs372429157

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465945	SCV000547490	uncertain significance	Colorectal cancer, susceptibility to, 10	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 566 of the POLD1 protein (p.Glu566Lys). This variant is present in population databases (rs372429157, gnomAD 0.008%). 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: 407947). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000608483	SCV000731310	uncertain significance	not specified	2016-12-28	criteria provided, single submitter	clinical testing	The p.Glu566Lys variant in POLD1 has not been previously reported in individuals with colorectal cancer, but has been identified in 1/15260 of South Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs372429157). Computational prediction tools and conservation analysis d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Glu566Lys variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759214	SCV000888433	uncertain significance	not provided	2020-01-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000759214	SCV001804977	uncertain significance	not provided	2024-05-20	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV003168787	SCV003909051	likely benign	Hereditary cancer-predisposing syndrome	2024-03-07	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000608483	SCV004024320	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000465945	SCV005402241	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-01-11	criteria provided, single submitter	clinical testing	The POLD1 c.1696G>A (p.Glu566Lys) missense change has a maximum subpopulation frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has not been reported in the literature in individuals with POLD1-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	RCV004737516	SCV005350777	uncertain significance	POLD1-related disorder	2024-05-22	no assertion criteria provided	clinical testing	The POLD1 c.1696G>A variant is predicted to result in the amino acid substitution p.Glu566Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is listed as as likely benign and uncertain in the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/407947/). This variant could be benign. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.