ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2599G>A (p.Val867Ile)

gnomAD frequency: 0.00001  dbSNP: rs367680864
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084300 SCV000558760 benign Colorectal cancer, susceptibility to, 10 2024-01-28 criteria provided, single submitter clinical testing
GeneDx RCV000679499 SCV000567939 likely benign not provided 2021-04-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485458 SCV000601918 uncertain significance not specified 2016-09-08 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV000485458 SCV000806506 likely benign not specified 2018-01-15 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000485458 SCV002761073 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV003168898 SCV003908993 likely benign Hereditary cancer-predisposing syndrome 2022-11-20 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355436 SCV001550320 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The POLD1 p.Val867Ile variant was not identified in the literature. The variant was identified in dbSNP (rs367680864) as “with other allele” and ClinVar (classified as likely benign by Invitae and GeneDx; and as uncertain significance by PreventionGenetics and Quest Diagnostics). The variant was identified in control databases in 122 of 249,266 chromosomes (1 homozygous) at a frequency of 0.0005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 110 of 30,598 chromosomes (freq: 0.004, increasing the likelihood this could be a low frequency benign variant), Other in 4 of 6110 chromosomes (freq: 0.0007), and European in 8 of 112,218 chromosomes (freq: 0.00007), while it was not observed in the African, Latino, Ashkenazi Jewish, East Asian or Finnish populations. The p.Val867 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000679499 SCV001809412 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000679499 SCV001917474 likely benign not provided no assertion criteria provided clinical testing

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