ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.3157C>T (p.Arg1053Cys)

gnomAD frequency: 0.00002  dbSNP: rs779208942
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466428 SCV000547673 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-17 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 1053 of the POLD1 protein (p.Arg1053Cys). 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 missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 408119). 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.
GeneDx RCV000486360 SCV000571818 uncertain significance not provided 2023-03-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 25790293, 26832770, 33924881, 35264596)
Mendelics RCV000709592 SCV000839448 uncertain significance Familial colorectal cancer 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003960027 SCV004769438 uncertain significance POLD1-related condition 2023-11-13 criteria provided, single submitter clinical testing The POLD1 c.3157C>T variant is predicted to result in the amino acid substitution p.Arg1053Cys. This variant has been reported in an individual with breast cancer (Table S3, Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50920465-C-T). It is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/408119/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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