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 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Invitae RCV000034638 SCV000218705 benign not provided 2019-03-02 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).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212860 SCV000601865 likely benign not specified 2016-12-01 criteria provided, single submitter clinical testing
Color RCV000115712 SCV000686260 likely benign Hereditary cancer-predisposing syndrome 2015-11-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000034638 SCV000697404 likely benign not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.953A>G (p.Tyr318Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Tyr318 is located in the Ribosomal protein S5 domain 2-type fold of Mismatch repair endonuclease PMS2. This variant was found in 64/122478 control chromosomes at a frequency of 0.0005225, which is approximately 5 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this variant is likely a benign polymorphism. Although pseudogene interference could be a possibily, 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. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Benign/Likely Benign. Taken together, this variant is classified as Likely 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
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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