Submissions for variant NM_000251.3(MSH2):c.1933C>G (p.Gln645Glu)

gnomAD frequency: 0.00001  dbSNP: rs267607982

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115513	SCV000149422	uncertain significance	not provided	2020-05-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal or family history suggestive of Lynch syndrome (Tournier 2008); This variant is associated with the following publications: (PMID: 18561205, 26333163)
Invitae	RCV000540956	SCV000625331	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573883	SCV000669705	likely benign	Hereditary cancer-predisposing syndrome	2023-03-20	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	RCV000662923	SCV000785871	uncertain significance	Lynch syndrome 1	2017-12-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000573883	SCV000908319	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 645 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). A functional study reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in an individual with suspected Lynch syndrome, in which a tumor sample showed the loss of MLH1 and presence of MSH2 (PMID: 18561205 and Universal Mutation Database) and in at least two additional individuals associated with colorectal cancer (Leiden Open Variation Database). This variant has been identified in 3/251432 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.	RCV000662923	SCV004018394	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.
All of Us Research Program, National Institutes of Health	RCV003997155	SCV004825017	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 645 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). A functional study reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in an individual with suspected Lynch syndrome, in which a tumor sample showed the loss of MLH1 and presence of MSH2 (PMID: 18561205 and Universal Mutation Database) and in at least two additional individuals associated with colorectal cancer (Leiden Open Variation Database). This variant has been identified in 3/251432 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000115513	SCV001549240	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Gln645Glu variant was identified in the literature, although a frequency in an affected population was not provided. The variant was identified in dbSNP (ID: rs267607982) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as uncertain significance by InSiGHT expert panel (2013), Invitae, Ambry Genetics, GeneDx, Color and Counsyl), and UMD-LSDB (1x as likely neutral). The variant was identified in control databases in 3 of 246212 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33582 chromosomes (freq: 0.00003) and European Non-Finnish in 2 of 111674 chromosomes (freq: 0.00002), while it was not observed in the African, Ashkenazi Jewish, East Asian, European Finnish, Other, or South Asian populations. The p.Gln645 residue is located in the ATPase domain of the MSH2 protein (Kansikas, 2011) and is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, both an ex vivo splicing assay and RT-PCR analysis of patient RNA showed no effect on splicing (Tournier 2008). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.