ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1963G>A (p.Val655Ile) (rs549467183)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000662941 SCV000807673 uncertain significance Lynch syndrome I 2018-06-13 reviewed by expert panel curation MLH1 methylation, but tumour with all proteins absent by IHC, proficient in CIMRA
GeneDx RCV000115514 SCV000149423 uncertain significance not provided 2017-04-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1963G>A at the cDNA level, p.Val655Ile (V655I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant has been observed in at least one individual with early-onset colon cancer (Shirts 2016). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely not pathogenic, based on unpublished data (Thompson 2014). MSH2 Val655Ile was observed at an allele frequency of 0.104% (12/11572) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val655Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the APTase domain and the region of interaction with EXO1 (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Val655Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000210146 SCV000266196 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000217714 SCV000273748 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing In silico models in agreement (benign);Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other strong data supporting benign classification
Invitae RCV001080304 SCV000284129 benign Hereditary nonpolyposis colon cancer 2019-12-21 criteria provided, single submitter clinical testing
Counsyl RCV000662941 SCV000785899 likely benign Lynch syndrome I 2018-01-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000115514 SCV000806017 likely benign not provided 2017-05-10 criteria provided, single submitter clinical testing
Color RCV000217714 SCV000903533 benign Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780441 SCV000917691 likely benign not specified 2019-08-26 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1963G>A (p.Val655Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251324 control chromosomes, predominantly at a frequency of 0.00075 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.32 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1963G>A has been reported in the literature in sequencing studies among individuals affected with breast, colorectal and pancreatic cancers (example, Shirts_2016, Tung_2015, Shindo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported in the literature and at our laboratory (BRCA1 del exons 9-12, Tung_2015; ATM c.8264_8268delATAAG, p.Tyr2755fs*12, Internal testing data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories and one expert panel (InSIGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters have reported the variant with conflicting assessments (5 as benign/likely benign and 3 as a VUS). Based on the evidence outlined above, the variant was classified as likely benign.

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