ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1461C>G (p.Asp487Glu) (rs35107951)

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Total submissions: 12
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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 In silico models in agreement (benign);Other data supporting benign classification
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 2020-12-08 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 I 2016-03-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590052 SCV000696215 uncertain significance not provided 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The c.1461C>G (p.Asp487Glu) in MSH2 gene is a missense change that involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant of interest is located within the clamp domain, which is a region that also interacts with MSH3 and MSH6. The variant is present in control dataset of ExAC at a low frequency of 0.000025 (3/121534 chrs tested) which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0005). This variant has been observed in at least 3 pts with HNPCC without clear contributory causality effect of this variant into disease pathogenesis (lack of MLH1 and PMS2 possibly due to confirmed MLH1 promoter hypermethylation with retention of MSH2 signal via ICH). In functional studies this variant showed moderate reduction of MMR activity compared to wt control. Many reputable databases/clinical laboratories classified this variant as VUS. Taking together, the variant was classified as VUS.
PreventionGenetics,PreventionGenetics RCV000590052 SCV000806000 uncertain significance not provided 2017-01-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131869 SCV000910759 benign Hereditary cancer-predisposing syndrome 2016-04-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000411837 SCV001304349 uncertain significance Lynch syndrome I 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 Praxis fuer Humangenetik Tuebingen RCV000590052 SCV001747253 uncertain significance not provided 2021-04-01 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.

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