Submissions for variant NM_000251.3(MSH2):c.2533A>G (p.Lys845Glu)

dbSNP: rs63750571

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215108	SCV000276369	likely benign	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000524393	SCV000548259	benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215108	SCV000685051	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 845 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). Functional studies have shown that the equivalent variant in yeast has 81% of wild-type mismatch repair activity (PMID: 17720936), and 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 individuals affected with Lynch syndrome (PMID: 10777691) and other cancers (PMID: 31386297). In a colorectal case-control study, this variant was reported in 40/12503 cases & 74/23704 controls (PMID: 33309985). This variant has been identified in 1/251436 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.
Counsyl	RCV000662762	SCV000785556	uncertain significance	Lynch syndrome 1	2017-09-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000076497	SCV000837856	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000662762	SCV001135762	uncertain significance	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030485	SCV001193639	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174808	SCV001338156	uncertain significance	not specified	2020-02-14	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2533A>G (p.Lys845Glu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251436 control chromosomes in the gnomAD database. Furthermore, a frequency of 0.0025 in 4.7K Japanese individuals was reported (Japanese Multi Omics Reference Panel, jMorp). The observed variant frequency within Japanese control individuals in the jMorp database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00057), suggesting that the variant may be a benign polymorphism found primarily in populations of Japanese origin. c.2533A>G has been reported in the literature in individuals of Japanese/Asian origin affected with cancer including Lynch Syndrome and breast cancer (e.g. Kiyozumi_2019, Nomura_2000, Tung_2015). These reports do not provide unequivocal conclusions about the association of the variant with Lynch Syndrome. A co-occurrence with a pathogenic variant has been reported (BRIP1 c.2392C>T, p.Arg798X; internal testing). Experimental evidence evaluating an impact on protein function demonstrated the variant to have a defect in DNA mismatch repair assays but showed ability to interact with all MSH2 partners in yeast two-hybrid assay (Gammie_2007). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical and functional importance becomes available.
Sema4, Sema4	RCV000215108	SCV002534484	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-22	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662762	SCV004018369	uncertain significance	Lynch syndrome 1	2023-03-22	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.