ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000034638 SCV000149621 likely benign not provided 2021-04-14 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22703879, 25801821, 25151201, 26689913, 27498913, 27739435, 25479140, 22949387, 23376243)
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 2020-12-04 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 Health, Inc RCV000115712 SCV000686260 likely benign Hereditary cancer-predisposing syndrome 2015-11-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286642 SCV001473250 likely benign none provided 2020-03-23 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354089 SCV001548618 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 p.Tyr318Cys variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs139438201) as With other allele, ClinVar (classified as benign by Invitae; classified as likely benign by GeneDx, Ambry Genetics; classified as uncertain significance by LMMPHPM), databases. The variant was not identified in Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 108 of 277068 chromosomes at a frequency of 0.00039 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Tyr318 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the DNA mismatch repair protein, C-terminal DNA mismatch repair protein family Ribosomal protein S5 domain 2-type fold functional domains increasing the likelihood that it may have clinical significance. In addition, the variant was found in Allelotypic analysis of novel nsSNPs and was found in 4 (1 homozygous) of 410 AJ controls and in 10 of 390 centenarians. The p.Y318C variant showed significant enrichment (5.3 fold, p=0.02) in PMS2 (Han 2013). 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.