ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1233G>C (p.Gln411His)

gnomAD frequency: 0.00004  dbSNP: rs771349646
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000645787 SCV000767542 uncertain significance Colorectal cancer, susceptibility to, 10 2023-12-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 411 of the POLD1 protein (p.Gln411His). This variant is present in population databases (rs771349646, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 537046). 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 RCV001571160 SCV001795579 uncertain significance not provided 2020-10-22 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal and family history of colorectal cancer as well as a personal history of melanoma (Raskin 2017); This variant is associated with the following publications: (PMID: 29056344, 29212164)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001571160 SCV002046598 uncertain significance not provided 2021-01-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV002360597 SCV002661868 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-21 criteria provided, single submitter clinical testing The p.Q411H variant (also known as c.1233G>C), located in coding exon 9 of the POLD1 gene, results from a G to C substitution at nucleotide position 1233. The glutamine at codon 411 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in one patient with melanoma diagnosed at age 28 and microsatellite stable colorectal cancer diagnosed at age 58 (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV000645787 SCV004203468 uncertain significance Colorectal cancer, susceptibility to, 10 2023-09-11 criteria provided, single submitter clinical testing

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