ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2516A>G (p.His839Arg) (rs63750027)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166332 SCV000217118 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000524390 SCV000259843 likely benign Hereditary nonpolyposis colon cancer 2017-11-08 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000076492 SCV000266197 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000486446 SCV000565203 uncertain significance not provided 2018-12-07 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2516A>G at the cDNA level, p.His839Arg (H839R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). MSH2 His839Arg was observed in two unrelated individuals, each with a personal and family history of colorectal cancer, one of whom also harbored a pathogenic MLH1 variant, and was also identified in five cancer-free relatives of the second individual (Yuan 2004, Tang 2009). This variant has also been observed in a breast cancer patient (Shirts 2016). In vitro functional studies demonstrated reduced mRNA expression, protein expression, and cell viability, but no significant defects in DNA damage signaling responses conferred by this variant (Arora 2017). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as having uncertain significance (Thompson 2014). MSH2 His839Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. MSH2 His839Arg is located in the ATPase domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 His839Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000765673 SCV000897015 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000166332 SCV000911047 likely benign Hereditary cancer-predisposing syndrome 2017-01-04 criteria provided, single submitter clinical testing

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