Submissions for variant NM_000535.7(PMS2):c.1489G>A (p.Gly497Ser)

gnomAD frequency: 0.00004  dbSNP: rs749826312

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464024	SCV000551927	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 497 of the PMS2 protein (p.Gly497Ser). This variant is present in population databases (rs749826312, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411016). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000573656	SCV000664899	likely benign	Hereditary cancer-predisposing syndrome	2018-09-04	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	RCV000573656	SCV000903920	likely benign	Hereditary cancer-predisposing syndrome	2024-10-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001597142	SCV001830862	uncertain significance	not provided	2024-03-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30877237)
All of Us Research Program, National Institutes of Health	RCV004001872	SCV004844200	likely benign	Lynch syndrome	2024-08-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800416	SCV005422996	uncertain significance	not specified	2024-10-07	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1489G>A (p.Gly497Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251408 control chromosomes. However, this observation needs to be cautiously considered since sequence alignment analysis suggests that the variant lies within a region of the gene that has high homology with the PMS2 pseudogene. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1489G>A in individuals affected with PMS2-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 411016). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005044691	SCV005674323	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2024-06-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005044691	SCV006053455	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2024-02-15	criteria provided, single submitter	clinical testing