Submissions for variant NM_000179.3(MSH6):c.532C>T (p.Arg178Cys)

gnomAD frequency: 0.00003  dbSNP: rs730881813

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160711	SCV000211342	uncertain significance	not provided	2020-08-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or ovarian cancer (Pal 2012, Terui 2013, Kiyozumi 2019); This variant is associated with the following publications: (PMID: 23047549, 24100870, 31386297, 31470354)
Ambry Genetics	RCV000217717	SCV000277057	likely benign	Hereditary cancer-predisposing syndrome	2018-11-01	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	RCV000456306	SCV000551096	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217717	SCV000685499	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 178 of the MSH6 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with pancreatic, ovarian, colorectal cancer, or Lynch syndrome (PMID: 23047549, 24100870, 31386297, 32973888, 32980694), as well as in healthy control individuals (PMID: 32980694). In one individual affected with colorectal cancer, this variant co-occurred with a pathogenic MSH2 variant (PMID: 24100870). In a large colorectal cancer case-control study, this variant was reported in 28/12503 cases & 36/23705 controls (PMID: 33309985). This variant has also been identified in 6/282830 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	RCV000781604	SCV000919776	uncertain significance	not specified	2018-11-23	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.532C>T (p.Arg178Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 277170 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.532C>T has been reported in the literature in individuals affected with ovarian cancer or colorectal cancer (Pal_2012, Terui_2013). Terui_2013 also reports the variant to co-occur with a likely pathogenic MSH2 variant, c.1915C>T (p.His639Tyr), which provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant three times as uncertain significance and once as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000986705	SCV001135788	uncertain significance	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030488	SCV001193642	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160711	SCV001469832	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)), breast cancer (PMIDs: 35449176 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)), colorectal cancer (PMIDs: 24100870 (2013), 31386297 (2019), 33309985 (2020)), acute myeloid leukemia (PMID: 31470354 (2019)), and biliary tract cancer (PMID: 36243179 (2022)). It has also been reported in healthy individuals (PMIDs: 36243179 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.00025 (5/19952 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000217717	SCV002536326	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-21	criteria provided, single submitter	curation
Baylor Genetics	RCV003467255	SCV004197605	uncertain significance	Endometrial carcinoma	2023-10-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998510	SCV004838851	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 178 of the MSH6 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with pancreatic, ovarian, colorectal cancer, or Lynch syndrome (PMID: 23047549, 24100870, 31386297, 32973888, 32980694), as well as in healthy control individuals (PMID: 32980694). In one individual affected with colorectal cancer, this variant co-occurred with a pathogenic MSH2 variant (PMID: 24100870). In a large colorectal cancer case-control study, this variant was reported in 28/12503 cases & 36/23705 controls (PMID: 33309985). This variant has also been identified in 6/282830 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.