Submissions for variant NM_000251.3(MSH2):c.1461C>G (p.Asp487Glu)

gnomAD frequency: 0.00011  dbSNP: rs35107951

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131869	SCV000186924	likely benign	Hereditary cancer-predisposing syndrome	2018-05-25	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.
GeneDx	RCV000590052	SCV000211181	likely benign	not provided	2021-01-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22290698, 22581703, 16885385, 15872200, 25559809, 23047549, 23718828, 26845104, 26333163, 21153778, 29641532)
Invitae	RCV000524343	SCV000218787	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000076170	SCV000266192	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000411837	SCV000488403	uncertain significance	Lynch syndrome 1	2016-03-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797621	SCV000696215	likely benign	not specified	2023-02-21	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1461C>G (p.Asp487Glu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Bioinformatic approaches evaluating functional effects for 168 MMR missense variants have predicted this variant to be neutral (example, Ali_2012).The variant allele was found at a frequency of 4.4e-05 in 251594 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (4.4e-05 vs 0.00057), allowing no conclusion about variant significance. c.1461C>G has been reported in the literature among individuals with colorectal cancer who did not fulfill either Amsterdam-II nor Bethesda criteria, had low MSI, normal MSH2 staining on IHC and hypermethylation of MLH1 promoter suggestive of a sporadic etiology of disease (example, Hampel_2005, Hampel_2006). It has also been reported as a VUS in settings of multigene panel testing of cohorts with colorectal/epithelial ovarian cancer (example, Chubb_2015, Pal_2012) These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Kantelinen_2012). The most pronounced variant effect results in approximately 50% of normal in vitro MMR activity. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=4; VUS, n=7). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000590052	SCV000806000	uncertain significance	not provided	2017-01-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131869	SCV000910759	likely benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000411837	SCV001304349	uncertain significance	Lynch syndrome 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000590052	SCV001747253	uncertain significance	not provided	2021-04-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798266	SCV002042091	uncertain significance	Breast and/or ovarian cancer	2022-05-04	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000131869	SCV000805266	uncertain significance	Hereditary cancer-predisposing syndrome	2018-06-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590052	SCV001551981	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Asp487Glu variant was identified in 4 of 9048 proband chromosomes (frequency: 0.0004) from individuals or families with endometrial, ovarian, or breast cancer and was not identified in 280 control chromosomes from healthy individuals (Hampel 2006, Pal 2012, Chubb 2015, Shirts 2015). The variant was also identified in the following databases: dbSNP (ID: rs35107951), ClinVar and Clinvitae (classified 5x as uncertain significance by InSiGHT, GeneDx, Invitae, University of Washington, Counsyl; classified 1x as likely benign by Ambry Genetics), Insight Colon Cancer Gene Variant Database (1x uncertain significance), Insight Hereditary Tumors Database (1x uncertain significance). The variant was not identified in the COGR, COSMIC, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant databases. The variant was identified in control databases in 13 of 277100 chromosomes at a frequency of 0.00005 in the following populations: European non-Finnish 12 of 126606 chromosomes (freq. 0.00009) and African in 1 of 24036 chromosomes (freq. 0.00004) (Genome Aggregation Consortium Feb 27, 2017). An in vitro functional study found this variant’s repair efficiency to be significantly decreased measured at 10% relative to wild type MSH2 (Kantelinen 2012). The p.Asp487Glu residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. An in silico classification tool (PON-MMR2) developed specifically for mismatch repair variants classified this variant as benign (Niroula 2015). The variant is located within the DNA mismatch repair protein MutS core, MutS clamp, and MSH2 functional domains. 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.
Genetic Services Laboratory, University of Chicago	RCV001797621	SCV003839738	uncertain significance	not specified	2022-07-29	no assertion criteria provided	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1461C>G, in exon 9 that results in an amino acid change, p.Asp487Glu. This sequence change does not appear to have been previously described in individuals with MSH2-related disorders and has been described in the gnomAD database with a frequency of 0.0046% in the overall population (dbSNP rs35107951). The p.Asp487Glu change affects a poorly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Asp487Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp487Glu change remains unknown at this time.