Submissions for variant NM_000535.7(PMS2):c.695G>A (p.Gly232Glu)

dbSNP: rs201811667

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034633	SCV000279321	uncertain significance	not provided	2018-01-02	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.695G>A at the cDNA level, p.Gly232Glu (G232E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGG>GAG). This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). PMS2 Gly232Glu was not observed in large population cohorts (Lek 2016). PMS2 Gly232Glu is located within the ATPase domain (Guarne 2001). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Gly232Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000569102	SCV000663473	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-10	criteria provided, single submitter	clinical testing	The p.G232E variant (also known as c.695G>A), located in coding exon 6 of the PMS2 gene, results from a G to A substitution at nucleotide position 695. The glycine at codon 232 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000662682	SCV000785392	uncertain significance	Lynch syndrome 4	2017-08-02	criteria provided, single submitter	clinical testing
Invitae	RCV000800172	SCV000939872	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-17	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 232 of the PMS2 protein (p.Gly232Glu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 41717). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193966	SCV001363162	uncertain significance	not specified	2019-05-06	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.695G>A (p.Gly232Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.695G>A has been reported in the literature in an individual affected with atherosclerosis (Johnston_2012). This report however, does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000662682	SCV004019891	uncertain significance	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662682	SCV004207823	uncertain significance	Lynch syndrome 4	2023-06-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569102	SCV004359668	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 232 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant has no significant impact on PMS2 protein expression, and the mutant protein had similar mismatch repair efficient and ATPase activity compared to wild type protein (PMID: 35189042). To our knowledge, this variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified 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.
All of Us Research Program, National Institutes of Health	RCV003996174	SCV004833798	uncertain significance	Lynch syndrome	2023-05-08	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034633	SCV000043435	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.