Submissions for variant NM_000535.7(PMS2):c.1233A>C (p.Glu411Asp)

dbSNP: rs587780040

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227364	SCV000285053	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 411 of the PMS2 protein (p.Glu411Asp). This variant is not present in population databases (gnomAD no frequency). 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: 237881). 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	RCV000567547	SCV000670869	likely benign	Hereditary cancer-predisposing syndrome	2024-02-19	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759913	SCV000889608	uncertain significance	not provided	2017-11-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000567547	SCV000905250	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-31	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 411 of the PMS2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 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.
Baylor Genetics	RCV003463655	SCV004205355	uncertain significance	Lynch syndrome 4	2023-10-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806260	SCV005429598	uncertain significance	Lynch syndrome	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 411 of the PMS2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 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.