Submissions for variant NM_000179.3(MSH6):c.3260C>A (p.Pro1087His)

dbSNP: rs63750753

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589544	SCV000149319	likely benign	not provided	2021-04-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10537275, 24728327, 23621914, 27398995, 26689913, 17594722, 10508506, 17531815, 22851212, 12019211, 21120944, 22102614, 29596542, 30072391)
Ambry Genetics	RCV000115410	SCV000184771	likely benign	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV000168382	SCV000219073	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115410	SCV000537572	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-02	criteria provided, single submitter	clinical testing	This missense variant replaces proline with histidine 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer (PMID: 27398995), breast cancer (PMID: 26689913, 32068069, 32658311), gastric cancer (PMID: 26689913), acute myeloid leukemia (PMID: 26689913), or colorectal cancer (PMID: 30072391), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 35/282836 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589544	SCV000601568	uncertain significance	not provided	2023-08-14	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 30072391 (2018), 35904628 (2022)), gastric cancer (PMID: 26689913 (2015)), endometrial cancer (PMID: 27398995 (2016)), and breast cancer (PMIDs: 26689913 (2015), 32068069 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.00051 (18/35424 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121584	SCV000695851	uncertain significance	not specified	2023-02-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3260C>A (p.Pro1087His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 252794 control chromosomes, predominantly at a frequency of 0.00052 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4 fold of the estimated maximal predicted allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3260C>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer, endometrial cancer and colorectal cancer (example, Lu_2015, Kanchi_2014, Rubio_2016, Patel_2018, Kwong_2020, Ackay_2021, Djursby_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics, part of Exact Sciences	RCV004528800	SCV000805886	uncertain significance	MSH6-related disorder	2023-06-14	criteria provided, single submitter	clinical testing	The MSH6 c.3260C>A variant is predicted to result in the amino acid substitution p.Pro1087His. This variant has been reported in individuals with endometrial cancer (Rubio et al. 2016. PubMed ID: 27398995) breast cancer (Kwong et al. 2020. PubMed ID: 32068069) colon cancer (Patel et al. 2018. PubMed ID: 30072391) and various other cancer types (Lu et al. 2015. PubMed ID: 26689913). However, this variant was also reported in individuals from a healthy control cohort (Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48030646-C-A). In ClinVar, this variant has conflicting interpretations of pathogenicity, from likely benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127584/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589544	SCV002010095	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001787917	SCV002030249	uncertain significance	Mismatch repair cancer syndrome 1	2021-02-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Centogene AG - the Rare Disease Company	RCV001808341	SCV002059505	uncertain significance	Lynch syndrome 5	2020-01-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115410	SCV002527997	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121584	SCV002552335	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997248	SCV004835030	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with histidine 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer (PMID: 27398995), breast cancer (PMID: 26689913, 32068069, 32658311), gastric cancer (PMID: 26689913), acute myeloid leukemia (PMID: 26689913), or colorectal cancer (PMID: 30072391), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 35/282836 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.
ITMI	RCV000121584	SCV000085780	not provided	not specified	2013-09-19	no assertion provided	reference population
Mayo Clinic Laboratories, Mayo Clinic	RCV000121584	SCV000691937	uncertain significance	not specified		no assertion criteria provided	clinical testing