ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.953A>G (p.Tyr318Cys) (rs139438201)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212860 SCV000149621 likely benign not specified 2018-01-20 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.
Ambry Genetics RCV000115712 SCV000183983 likely benign Hereditary cancer-predisposing syndrome 2018-12-13 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Invitae RCV001083014 SCV000218705 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212860 SCV000540070 uncertain significance not specified 2016-10-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified as DP in HGMD. It has been seen in one 4 control alleles and 10 centenarian alleles in one study. It is classified in ClinVar with 2 stars as Likely benign/benign by 4 submitters (Invitae, Ambry, GeneDx, Biesecker lab). MaxMAF = 0.05% in ExAC (high for disease incidence).
Color RCV000115712 SCV000686260 likely benign Hereditary cancer-predisposing syndrome 2015-11-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212860 SCV000697404 benign not specified 2020-02-27 criteria provided, single submitter clinical testing Variant summary: PMS2 c.953A>G (p.Tyr318Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein, C-terminal (IPR013507) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 254040 control chromosomes. Although pseudogene interference cannot be completely ruled out, this allele frequency is likely accurate because there are several mismatches between PMS2 and the pseudogene within 25 bases upstream of the variant of interest, increasing the likelihood of specificity. The observed variant frequency is approximately 4.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. c.953A>G has been reported in the literature in sequencing studies of individuals affected with prostrate cancer, healthy AJ centenarians with no evidence of cancer, and BRCA testing cohorts (example, Grant_2015, Han_2013, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least two co-occurrences with other pathogenic variants have been reported (BRCA1 c.68_69del, p.Glu23ValfsX17)(Tung_2015) and MSH6 c.3984_3987dupGTCA, p.Leu1330fsX12 at our laboratory), providing additional supporting evidence for a benign role. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign (1)/likely benign(7), n=8 and VUS, n=3). Based on the evidence outlined above, the variant was re-classified from likely benign to benign.
Mendelics RCV000708989 SCV000838185 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034638 SCV000888423 benign not provided 2018-11-09 criteria provided, single submitter clinical testing
Mendelics RCV000987839 SCV001137309 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000987839 SCV001326415 likely benign Hereditary nonpolyposis colorectal cancer type 4 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034638 SCV000043431 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
True Health Diagnostics RCV000115712 SCV000788121 likely benign Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing

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