Submissions for variant NM_000251.3(MSH2):c.885C>G (p.Asp295Glu)

gnomAD frequency: 0.00005  dbSNP: rs201334592

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220130	SCV000274132	likely benign	Hereditary cancer-predisposing syndrome	2018-09-29	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.
Counsyl	RCV000411007	SCV000489642	uncertain significance	Lynch syndrome 1	2016-11-02	criteria provided, single submitter	clinical testing
Invitae	RCV000469366	SCV000548203	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000589679	SCV000567699	uncertain significance	not provided	2021-07-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18822302, 21120944, 30212499, 23047549, 29684080)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589679	SCV000696292	uncertain significance	not provided	2017-05-26	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.885C>G (p.Asp295Glu) variant located in the DNA mismatch repair protein MutS, connector domain (via InterPro) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 7/121246 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). A publication, Pal_2012, cites the variant in an affected individual with limited information (ie, lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories report the variant with conflicting classifications, "likely benign" or "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Color Diagnostics, LLC DBA Color Health	RCV000220130	SCV000903130	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 295 of the MSH2 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549) and an individual affected with kidney carcinoma (PMID: 29684080). This variant has also been identified in 12/251032 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.
Myriad Genetics, Inc.	RCV000411007	SCV004018229	likely benign	Lynch syndrome 1	2023-03-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000411007	SCV004196278	uncertain significance	Lynch syndrome 1	2023-08-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997848	SCV004831588	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 295 of the MSH2 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549) and an individual affected with kidney carcinoma (PMID: 29684080). This variant has also been identified in 12/251032 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.