ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2103C>T (p.Tyr701=)

gnomAD frequency: 0.00029  dbSNP: rs201483538
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079593 SCV000287553 benign Colorectal cancer, susceptibility to, 10 2021-12-17 criteria provided, single submitter clinical testing
GeneDx RCV000434365 SCV000519115 likely benign not specified 2017-09-12 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679489 SCV000601905 benign not provided 2019-02-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000575474 SCV000670945 likely benign Hereditary cancer-predisposing syndrome 2015-07-21 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.
PreventionGenetics,PreventionGenetics RCV000679489 SCV000806490 likely benign not provided 2017-08-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000434365 SCV000918080 benign not specified 2018-12-14 criteria provided, single submitter clinical testing Variant summary: POLD1 c.2103C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00085 in 119288 control chromosomes in the ExAC database, including 1 homozygote. The observed variant frequency is approximately 60 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2103C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (5x). Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory,University of Chicago RCV000434365 SCV002065994 likely benign not specified 2018-11-09 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000575474 SCV002534620 likely benign Hereditary cancer-predisposing syndrome 2021-05-01 criteria provided, single submitter curation
True Health Diagnostics RCV000575474 SCV000788136 likely benign Hereditary cancer-predisposing syndrome 2017-09-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356425 SCV001551589 likely benign Carcinoma of colon no assertion criteria provided clinical testing The POLD1 p.Tyr701= variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in the following databases: dbSNP (ID: rs201483538) as “With Likely benign allele “, ClinVar and Clinvitae (4x as benign by Invitae, and as likely benign by GeneDx, Quest Diagnostics and Ambry Genetics). The variant was identified in control databases in 195 of 276096 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African in 2 of 23960 chromosomes (freq: 0.00008), “Other” in 2 of 6448 chromosomes (freq: 0.0003), Latino in 6 of 34352 chromosomes (freq: 0.0002), European Non-Finnish in 76 of 125882 chromosomes (freq: 0.0006), European Finnish in 6 of 25776 chromosomes (freq: 0.0002), and South Asian in 103 of 30756 chromosomes (freq: 0.003). While the variant was not observed in the Ashkenazi Jewish or East Asian populations. The p.Tyr701= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000434365 SCV002551948 likely benign not specified 2021-12-03 no assertion criteria provided clinical testing

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