Submissions for variant NM_002691.4(POLD1):c.1291A>G (p.Ile431Val)

gnomAD frequency: 0.00001  dbSNP: rs752444746

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000576076	SCV000671134	likely benign	Hereditary cancer-predisposing syndrome	2023-01-05	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645834	SCV000767589	uncertain significance	Colorectal cancer, susceptibility to, 10	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 431 of the POLD1 protein (p.Ile431Val). This variant is present in population databases (rs752444746, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 484376). 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.
Fulgent Genetics, Fulgent Genetics	RCV000764218	SCV000895221	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001591338	SCV001814657	uncertain significance	not provided	2024-05-24	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; This variant is associated with the following publications: (PMID: 29056344, 20951805)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001591338	SCV002774217	likely benign	not provided	2022-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317289	SCV004020887	uncertain significance	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.1291A>G (p.Ile431Val) results in a conservative amino acid change located in the exonuclease domain (IPR006133) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251358 control chromosomes (gnomAD). The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing colorectal cancer (1.4e-05), however due to the presence of the POLD1 pseudogene this should be interpreted with caution and does not necessarily allow any conclusion about variant significance. To our knowledge, no occurrence of c.1291A>G in individuals affected with colorectal cancer or other POLD1-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.