ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.197C>G (p.Ala66Gly)

gnomAD frequency: 0.00002  dbSNP: rs199792522
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000460501 SCV000547601 uncertain significance Colorectal cancer, susceptibility to, 10 2025-01-01 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 66 of the POLD1 protein (p.Ala66Gly). This variant is present in population databases (rs199792522, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 408049). 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 RCV000485401 SCV000569834 uncertain significance not provided 2025-05-05 criteria provided, single submitter clinical testing Observed in a patient with breast cancer (PMID: 35264596); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35264596)
Mendelics RCV003492057 SCV001141126 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV003168791 SCV003909022 likely benign Hereditary cancer-predisposing syndrome 2024-12-09 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.

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