ClinVar Miner

Submissions for variant NM_000179.3(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
GeneDx RCV000586012 SCV000211359 likely benign not provided 2020-10-26 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10508506, 22102614, 22851212, 23621914, 24362816, 21120944, 24040339, 12019211, 26333163)
Ambry Genetics RCV000160725 SCV000216588 likely benign Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence;Other data supporting benign classification
Invitae RCV000524164 SCV000254311 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586012 SCV000601569 uncertain significance not provided 2020-04-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160725 SCV000685377 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-13 criteria provided, single submitter clinical testing This missense variant replaces proline with arginine at codon 1087 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant has normal mismatch repair function, binding with MSH2, and nuclear localization (PMID: 12019211, 22102614, 22851212, 24040339). This variant has been observed in individuals affected with colorectal and endometrial cancer (PMID: 10508506, 31307542). This variant has been identified in 14/282836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Mendelics RCV000074829 SCV000837912 uncertain significance Lynch syndrome 2018-07-02 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

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