ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3260C>G (p.Pro1087Arg) (rs63750753)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160725 SCV000216588 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting benign classification
Color RCV000160725 SCV000685377 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764430 SCV000895487 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000212680 SCV000211359 likely benign not specified 2018-01-10 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.
Integrated Genetics/Laboratory Corporation of America RCV000586012 SCV000695852 uncertain significance not provided 2016-03-07 criteria provided, single submitter clinical testing Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and hydrophobic Proline (P) with a large size and basic Arginine (R). 4/5 in silico tools predict the variant to be disease causing. The variant was observed in the Latino and Non-Finnish European subcohorts of the ExAC project at an allele frequency of 0.0064% which does not exceed the maximal expected allele frequency of a disease causing MSH6 allele (0.014%). The variant was reported in an HNPCC kindred that did not fulfill the Amsterdam criteria without strong evidence for pathogenicity (Kariola_HumMolGenet_2002). Independent functional studies assessing the variant for MMR proficiency, localization and impact on MSH6- MSH2 binding demonstrated no significance difference between WT MSH6 and MSH6 P1087R proteins (Belvederesi_FC_2012,Drost_MSH2_HM_2011, Kariola_HumMolGenet_2002, Wielders_PolsOne_2013). Clinical laboratories classify variant as Uncertain or Likely Benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as a VUS-possibly benign until more information becomes available.
Invitae RCV000524164 SCV000254311 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 1087 of the MSH6 protein (p.Pro1087Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs63750753, ExAC 0.009%). This variant has been reported in the literature in an individual affected with colon cancer (PMID: 10508506). ClinVar contains an entry for this variant (Variation ID: 89362). Experimental studies have shown that this missense change does not disrupt MSH6 mismatch repair function, interaction with MSH2, or cellular localization (PMID: 12019211, 22102614, 22851212, 24040339). 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.
Mendelics RCV000074829 SCV000837912 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212680 SCV000601569 uncertain significance not specified 2017-05-10 criteria provided, single submitter clinical testing

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