Submissions for variant NM_000251.3(MSH2):c.166G>A (p.Glu56Lys)

dbSNP: rs587779102

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122982	SCV000166265	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 56 of the MSH2 protein (p.Glu56Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer and colorectal cancer (PMID: 23047549, 31997046). ClinVar contains an entry for this variant (Variation ID: 135854). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. 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.
GeneDx	RCV000657006	SCV000292792	uncertain significance	not provided	2023-10-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with ovarian cancer and another with colorectal cancer whose tumor retained MSH2 expression on immunohistochemistry (PMID: 31997046, 23047549); Published functional studies demonstrate sensitivity to 6-thioguanine, suggesting intact mismatch repair function (PMID: 33357406); This variant is associated with the following publications: (PMID: 31997046, 23047549, 18822302, 21120944, 33357406)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000235661	SCV000539688	uncertain significance	not specified	2016-06-16	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in proband with ovarian cancer; ClinVar: 1 VUS
Color Diagnostics, LLC DBA Color Health	RCV000580136	SCV000684962	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 56 of the MSH2 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). 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 colon cancer (PMID: 31997046). 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.
Ambry Genetics	RCV000580136	SCV001173134	likely benign	Hereditary cancer-predisposing syndrome	2021-12-16	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235661	SCV002760629	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477321	SCV002777701	uncertain significance	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-03-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460870	SCV004196187	uncertain significance	Lynch syndrome 1	2023-10-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997405	SCV004831950	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 56 of the MSH2 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). 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 colon cancer (PMID: 31997046). 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.