Submissions for variant NM_002691.4(POLD1):c.1322C>T (p.Thr441Met)

gnomAD frequency: 0.00005  dbSNP: rs376711125

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226871	SCV000287511	uncertain significance	Colorectal cancer, susceptibility to, 10	2025-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 441 of the POLD1 protein (p.Thr441Met). This variant is present in population databases (rs376711125, gnomAD 0.02%). 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: 239230). 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.
GeneDx	RCV000480965	SCV000569283	uncertain significance	not provided	2024-04-01	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: 27071721, 24265153, 25228659, 20951805)
Ambry Genetics	RCV000575300	SCV000670968	likely benign	Hereditary cancer-predisposing syndrome	2024-03-11	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.
Fulgent Genetics, Fulgent Genetics	RCV000764220	SCV000895223	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000480965	SCV001152023	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	POLD1: BP4
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267982	SCV002551911	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480965	SCV004219056	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00023 (8/35422 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
True Health Diagnostics	RCV000575300	SCV000788127	uncertain significance	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing