ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.13C>T (p.Arg5Trp)

gnomAD frequency: 0.00038  dbSNP: rs9282830
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079499 SCV000287516 likely benign Colorectal cancer, susceptibility to, 10 2024-01-27 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000732271 SCV000860198 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000732271 SCV001134626 benign not provided 2019-07-23 criteria provided, single submitter clinical testing
GeneDx RCV000732271 SCV001790019 uncertain significance not provided 2021-03-30 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Genetic Services Laboratory, University of Chicago RCV001818598 SCV002070050 uncertain significance not specified 2020-01-03 criteria provided, single submitter clinical testing DNA sequence analysis of the POLD1 gene demonstrated a sequence change, c.13C>T, in exon 2 that results in an amino acid change, p.Arg5Trp. This sequence change does not appear to have been previously described in patients with POLD1-related disorders and has been described in the gnomAD database with a frequency of 0.10% in African populations (dbSNP rs9282830). The p.Arg5Trp change affects a highly conserved amino acid residue located in a domain of the POLD1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg5Trp substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg5Trp change remains unknown at this time.
Sema4, Sema4 RCV002257545 SCV002534582 likely benign Hereditary cancer-predisposing syndrome 2020-10-09 criteria provided, single submitter curation
Ambry Genetics RCV002257545 SCV003909062 likely benign Hereditary cancer-predisposing syndrome 2022-11-11 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.
PreventionGenetics, part of Exact Sciences RCV004541392 SCV004785453 likely benign POLD1-related disorder 2023-06-16 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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