Submissions for variant NM_002691.4(POLD1):c.934G>A (p.Val312Met)

gnomAD frequency: 0.00006  dbSNP: rs371612922

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759972	SCV000293919	uncertain significance	not provided	2023-11-16	criteria provided, single submitter	clinical testing	In silico analysis supports 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: 21157497, 34183866, 20951805)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474151	SCV000547597	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-02-01	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 312 of the POLD1 protein (p.Val312Met). This variant is present in population databases (rs371612922, gnomAD 0.009%). 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: 246387). 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.
Ambry Genetics	RCV000565647	SCV000671012	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-21	criteria provided, single submitter	clinical testing	The p.V312M variant (also known as c.934G>A), located in coding exon 7 of the POLD1 gene, results from a G to A substitution at nucleotide position 934. The valine at codon 312 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759972	SCV000889701	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	The POLD1 c.934G>A (p.Val312Met) variant has been reported in the published literature as one of several germline variants in an individual with colorectal cancer (PMIDs: 31769227 (2020)) and in an individual with obsessive-compulsive disorder (PMID: 34183866 (2021)). The frequency of this variant in the general population, 0.000056 (7/125888 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000759972	SCV002010598	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000565647	SCV002534714	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-03	criteria provided, single submitter	curation
Baylor Genetics	RCV000474151	SCV004203460	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-03-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016647	SCV005650290	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome; Immunodeficiency 120	2024-06-13	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483598	SCV004228733	not provided	Familial colorectal cancer; Mandibular hypoplasia-deafness-progeroid syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.