Submissions for variant NM_000535.7(PMS2):c.755G>A (p.Cys252Tyr)

gnomAD frequency: 0.00001  dbSNP: rs775445157

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000556803	SCV000625687	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564413	SCV000664900	likely benign	Hereditary cancer-predisposing syndrome	2022-06-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Color Diagnostics, LLC DBA Color Health	RCV000564413	SCV000686235	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 252 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 18/250288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781740	SCV000920028	uncertain significance	not specified	2018-02-16	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.755G>A (p.Cys252Tyr) results in a non-conservative amino acid change located in the C-terminal domain of PMS2 (IPR013507) that functions in promoting dimerization (InterPro). Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4.58 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 a benign polymorphism found primarily in populations of South Asian origin, however the technology utilized for this dataset does not rule out pseudogene interference and thus this data cannot be relied upon. To our knowledge, no occurrence of c.755G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with another likely pathogenic PMS2 variant have been found in two internal samples (PMS2 c.1908delA, p.Gln637fsX28), providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, this variant is classified as VUS-possibly benign, until additional information becomes available.
GeneDx	RCV001568558	SCV001792451	uncertain significance	not provided	2020-01-07	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV000781740	SCV002068399	uncertain significance	not specified	2018-03-02	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338645	SCV004047409	uncertain significance	Lynch syndrome 4		criteria provided, single submitter	clinical testing	The missense variant in c.755G>A (p.Cys252Tyr) in PMS2 gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. The p.Cys252Tyr variant is reported with the allele frequency of 0.007192% in gnomAD Exome and is novel (not in any individuals) in 1000 Genomes. The amino acid Cys at position 252 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Cys252Tyr in PMS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV004003768	SCV004839919	uncertain significance	Lynch syndrome	2023-07-22	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 252 of the PMS2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 18/250288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.