Submissions for variant NM_000179.3(MSH6):c.3260C>G (p.Pro1087Arg)

dbSNP: rs63750753

Total submissions: 10

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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000524164	SCV000254311	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	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 Diagnostics, LLC DBA Color Health	RCV000160725	SCV000685377	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	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 mutant protein has mismatch repair function, ability to bind with MSH2, and nuclear localization similar to wild type protein (PMID: 12019211, 22102614, 22851212, 24040339). This variant has been observed in individuals affected with colorectal and endometrial cancer (PMID: 10508506, 31307542), pancreatic cancer (PMID: 36230473), and breast and/or ovarian cancer (PMID: 34359559, 33471991). This variant has also been observed in healthy individuals (PMID: 34172528, 33471991). 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; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160725	SCV002527998	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-11	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149721	SCV003838324	uncertain significance	Breast and/or ovarian cancer	2022-03-24	criteria provided, single submitter	clinical testing