ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.815C>T (p.Ala272Val) (rs34136999)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076728 SCV000107764 benign Lynch syndrome 2018-10-18 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability <0.001
GeneDx RCV000212591 SCV000149451 likely benign not specified 2018-01-19 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001081902 SCV000166286 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115542 SCV000172868 likely benign Hereditary cancer-predisposing syndrome 2018-06-04 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
Genetic Services Laboratory, University of Chicago RCV000212591 SCV000595835 uncertain significance not specified 2017-03-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034559 SCV000601490 likely benign not provided 2020-07-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115542 SCV000690134 likely benign Hereditary cancer-predisposing syndrome 2015-06-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212591 SCV000696286 benign not specified 2021-06-06 criteria provided, single submitter clinical testing Variant summary: MSH2 c.815C>T (p.Ala272Val) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 252008 control chromosomes, predominantly at a frequency of 0.00041 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is close to that estimated for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00041 vs 0.00057), supporting a benign role for the variant of interest. c.815C>T has been reported in the literature in individuals affected with Lynch Syndrome, as well as colorectal-, pancreatic-, breast- and skin cancers (example, Lin_1999, Ollila_2006, Nilbert_2009, Samowitz_2001, Syngal_1999, Yang_2016, Dominguez-Valentin_2018, Cho_2018, Young_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. <ultiple co-occurrences with other pathogenic variants have been reported (MSH2 c.518T>G / p.Leu173Arg, in the UMD database; MLH1 del exon 6, Mueller_2009; BRCA2 c.9382C>T / p.Arg3128X, Domingues-Valentin_2018), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating the impact of MSH2 c.815C>T on protein function. The variant was shown to mildly affect the normal splicing pattern by causing exon 5 exclusion (Tournier_2008, Lastella_2006, Dominguez-Valentin_2018), however tumors in mutation carriers showed normal MSH2 expression (Ollila_2006). In addition, the variant was shown to be MMR-proficient by the in vitro MMR assay as reported by several independent research groups (Ollila_2006, Ollila_2008, Drost_2011). Taken together these results indicate that this variant does not significantly damage MSH2 protein function. Multiple clinical diagnostic laboratories and an expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments with the expert panel and five other submitters reporting a benign/likely benign outcome. Based on the absence of evidence supporting an actionable outcome in literature spanning over two decades of evolution as outlined above, the variant was re-classified as benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212591 SCV000711973 uncertain significance not specified 2019-01-31 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala272Val variant in MSH2 has been reported in at least 11 individuals with Lynch Syndrome-related cancers (Ollila 2006, Mueller 2009, InSiGHT database ( One of these patients carried a second pathogenic variant in MLH1. In vitro functional studies provide some evidence that the p.Ala272Val variant may have a slight impact on the protein (Tournier 2008, Lastella 2006), however others demonstrate an effect comparable to that in the wild-type (Ollila 2006). These types of assays may not accurately represent biological function. This variant has been identified in 11/10358 Ashkenazi Jewish chromosomes (0.1%) by the Genome Aggregation Consortium (GnomAD, Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In addition, it has been classified as Uncertain Significance on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107764.2). In summary, the clinical significance of the p.Ala272Val variant is uncertain.
Counsyl RCV000663110 SCV000786235 uncertain significance Lynch syndrome I 2018-03-26 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034559 SCV000806049 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing
Mendelics RCV000076728 SCV000837822 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000663110 SCV001135708 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034559 SCV000043336 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148632 SCV000190347 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357272 SCV001552691 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Ala272Val variant was identified in 1 of 1132 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Hampel 2005). The variant was also identified in dbSNP (ID: rs34136999) as “With other allele”, in ClinVar (classified as benign by Invitae; likely benign by GeneDx, Ambry Genetics, color Genomics; uncertain significance by 5 clinical laboratories), Clinvitae (conflicting interpretations of pathogenicity), MutDB, UMD-LSDB (classified as neutral), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. In UMD the variant was identified with a co-occurring pathogenic MSH2 variant (c.518T>G, p.Leu173Arg), increasing the likelihood that the p.Ala272Val variant does not have clinical significance. The variant was not identified in GeneInsight-COGR, Cosmic, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 77 of 276232 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 23984 chromosomes (freq: 0.0001), Other in 2 of 6438 chromosomes (freq: 0.0003), Latino in 14 of 34346 chromosomes (freq: 0.0004), European Non-Finnish in 49 of 126334 chromosomes (freq: 0.0004), Ashkenazi Jewish in 9 of 10140 chromosomes (freq: 0.001), and South Asian in 1 of 30510 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian, European Finnish, populations. Several functional studies demonstrated this variant resulted in partial exon 5 skipping (Lastella 2006, Tournier 2008) and slightly reduced mismatch binding of the MMR reaction (Ollila 2008). The variant showed no reduction in mismatch repair capability compared with the wild-type MSH2 (Ollila 2006). In addition, the variant was identified with a pathogenic BRCA2 c.9382C>T in a patient diagnosed with ductal carcinoma at 44 years of age (Dominguez-Valentin 2018). The p.Ala272 residue is conserved in mammals and 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 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. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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