Submissions for variant NM_002691.4(POLD1):c.2518G>A (p.Val840Met)

gnomAD frequency: 0.00001  dbSNP: rs763443242

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000551806	SCV000646570	uncertain significance	Colorectal cancer, susceptibility to, 10	2023-12-29	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 840 of the POLD1 protein (p.Val840Met). This variant is present in population databases (rs763443242, gnomAD 0.007%). 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: 469270). 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759947	SCV000889665	uncertain significance	not provided	2018-06-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000759947	SCV002013293	uncertain significance	not provided	2021-11-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29056344)
Ambry Genetics	RCV002431651	SCV002742002	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	clinical testing	The p.V840M variant (also known as c.2518G>A), located in coding exon 19 of the POLD1 gene, results from a G to A substitution at nucleotide position 2518. The valine at codon 840 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.