ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2316G>A (p.Met772Ile)

gnomAD frequency: 0.00002  dbSNP: rs750956986
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000805785 SCV000945753 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 772 of the POLD1 protein (p.Met772Ile). This variant is present in population databases (rs750956986, gnomAD 0.003%). This missense change has been observed in individual(s) with colon cancer (PMID: 28125075). ClinVar contains an entry for this variant (Variation ID: 650608). 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 RCV001759541 SCV001985761 uncertain significance not provided 2023-08-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with colon cancer (Ghazani et al., 2017); This variant is associated with the following publications: (PMID: 28125075)
PreventionGenetics, part of Exact Sciences RCV003947996 SCV004767142 uncertain significance POLD1-related condition 2024-01-29 criteria provided, single submitter clinical testing The POLD1 c.2316G>A variant is predicted to result in the amino acid substitution p.Met772Ile. This variant has been reported as a variant of uncertain significance in a patient with colon cancer (Table S9, Ghazani et al. 2017. PubMed ID: 28125075). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/650608/). 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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