ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.815C>T (p.Ala272Val) (rs34136999)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115542 SCV000172868 likely benign Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Other data supporting benign classification
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 Medical Center RCV000148632 SCV000190347 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Color RCV000115542 SCV000690134 likely benign Hereditary cancer-predisposing syndrome 2015-06-09 criteria provided, single submitter clinical testing
Counsyl RCV000663110 SCV000786235 uncertain significance Lynch syndrome I 2018-03-26 criteria provided, single submitter clinical testing
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.
Genetic Services Laboratory, University of Chicago RCV000212591 SCV000595835 uncertain significance not specified 2017-03-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000034559 SCV000696286 uncertain significance not provided 2016-11-25 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.815C>T (p.Ala272Val) variant located in the conserved connector domain involves the alteration of a conserved nucleotide, which 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 29/121370 control chromosomes at a frequency of 0.0002389, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). The variant was identified in patients with different clinical characteristics and co-occurred in at least one patient with a pathogenic MLH1 variant (Thompson_2013, Mueller_2009), a pathogenic MSH2 variant (UMD), and MLH1, c.244A>G (p.Thr82Ala - classified as likely pathogenic, Internal LCA sample). This variant was shown to mildly affect normal splicing pattern by causing 5-12% exon 5 exclusion, however tumors in mutation carriers showed normal MSH2 expression. In addition, this variant was shown to be MMR-proficient in the in vitro MMR assay by several independent research groups. Multiple reputable clinical labs and databases have classified the variant as VUS, with one exception, where it was classified as Benign, without evidence independently evaluate. More segregation data combined with extensive tumor characterization results needed to classify this variant with confidence. Taken together, this variant has been classified as VUS-possibly benign.
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
Invitae RCV000524422 SCV000166286 benign Hereditary nonpolyposis colon cancer 2017-12-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212591 SCV000711973 uncertain significance not specified 2016-11-30 criteria provided, single submitter clinical testing The p.Ala272Val variant in MSH2 has been reported in at least 11 individuals wit h Lynch Syndrome-related cancers (Ollila 2006, Mueller 2009, InSiGHT database (h ttp://chromium.lovd.nl/LOVD2/colon_cancer/variants.php)). 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 prot ein (Tournier 2008, Lastella 2006), however others demonstrate an effect compara ble to that in the wild-type (Ollila 2006). These types of assays may not accura tely represent biological function. This variant has been identified in 25/66572 European chromosomes (0.04%) by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs34136999). Computational prediction tools and c onservation analysis do not provide strong support for or against an impact to t he 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.
Mendelics RCV000076728 SCV000837822 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000034559 SCV000806049 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212591 SCV000601490 uncertain significance not specified 2017-05-27 criteria provided, single submitter clinical testing

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