Submissions for variant NM_002691.4(POLD1):c.3148C>T (p.Arg1050Cys)

gnomAD frequency: 0.00001  dbSNP: rs780749621

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645812	SCV000767567	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1050 of the POLD1 protein (p.Arg1050Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 537068). 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	RCV001799693	SCV002044212	uncertain significance	not provided	2021-06-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533)
Ambry Genetics	RCV002325271	SCV002608582	likely benign	Hereditary cancer-predisposing syndrome	2024-11-08	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000645812	SCV004015254	uncertain significance	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 1050 of the POLD1 protein (p.Arg1050Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not found in gnomAD genomes. This variant has not been reported in the literature in individuals with POLD1-related disease. In-silico predictions show pathogenic computational verdict based on 9 pathogenic predictions from PolyPhen, DANN, DEOGEN2, FATHMM-MKL, LIST-S2, M-CAP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs 3 benign predictions from BayesDel_addAF, EIGEN and MVP and it weakly conserved . Therefore, it has been classified as a Variant of Uncertain Significance.