ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1847C>G (p.Pro616Arg) (rs587779965)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212611 SCV000149421 uncertain significance not provided 2018-02-07 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1847C>G at the cDNA level, p.Pro616Arg (P616R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). This variant was observed in two pediatric cases of acute lymphoblastic leukemia, at least one individual with a family history of breast and/or ovarian cancer, an individual with colorectal cancer, and at least one additional individual with a personal history of a Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015, Zhang 2015, DeRycke 2017, Zidan 2017). MSH2 Pro616Arg was observed at an allele frequency of 0.03% (12/34,418) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located within the Lever domain, as well as in the regions of interaction with MSH6, MSH3, and EXO1 (Guerrette 1998, L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Pro616Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115512 SCV000172808 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000205979 SCV000260268 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 616 of the MSH2 protein (p.Pro616Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs587779965, ExAC 0.01%). This variant has been reported in individuals undergoing testing for suspected Lynch syndrome (PMID: 25980754, 28526081), individuals with acute lymphoblastic leukemia (PMID: 26580448), colorectal cancer (PMID: 28135145, 29212164), and an individual in the Universal Mutation Database (PMID: 23729658). However, in one of these individuals a pathogenic allele was also identified in MSH2 (PMID: 28526081), which suggests that this c.1847C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 127636). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000115512 SCV000292216 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing
Counsyl RCV000411841 SCV000489511 uncertain significance Lynch syndrome I 2016-10-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212611 SCV000806014 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing
Mendelics RCV000708836 SCV000837841 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212611 SCV001134346 uncertain significance not provided 2019-06-14 criteria provided, single submitter clinical testing

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