Submissions for variant NM_000179.3(MSH6):c.3772C>G (p.Gln1258Glu)

gnomAD frequency: 0.00003  dbSNP: rs63750554

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227470	SCV000283822	benign	Hereditary nonpolyposis colorectal neoplasms	2024-11-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000766490	SCV000569546	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or suspected Lynch syndrome (Ross 2017, Schneider 2018, Kiyozumi 2019, Wang 2019, Shin 2020); This variant is associated with the following publications: (PMID: 28932927, 28874130, 29575718, 30982232, 32019277, 31386297, 17531815, 21120944)
Ambry Genetics	RCV000491197	SCV000580142	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-21	criteria provided, single submitter	clinical testing	The p.Q1258E variant (also known as c.3772C>G), located in coding exon 8 of the MSH6 gene, results from a C to G substitution at nucleotide position 3772. The glutamine at codon 1258 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was detected in a Korean individual whose colorectal tumor was microsatellite stable (MSS) and demonstrated normal mismatch repair protein expression on immunohistochemistry (Kiyozumi Y et al. Cancer Med, 2019 Sep;8:5534-5543); however, this alteration was also detected in one family from Brazil with suspected Lynch syndrome (Rossi BM et al. BMC Cancer, 2017 Sep;17:623). This alteration was reported in a Brazilian individual with no features of CMRD who also had MLH1 p.Lys618Glu (Schneider NB et al. Cancer Med, 2018 05;7:2078-2088). This alteration was identified in a cohort of patients diagnosed with biliary tract carcinoma undergoing multigene panel testing for hereditary cancer risk (Terashima T et al. Oncotarget, 2019 Oct;10:5949-5957), as well as in 1/496 Korean patients with clinical features of hereditary breast and ovarian cancer syndrome (HBOC) (Shin HC et al. Cancer Res Treat, 2020 Jul;52:697-713). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766490	SCV000601585	uncertain significance	not provided	2024-10-30	criteria provided, single submitter	clinical testing	The MSH6 c.3772C (p.Gln1258Glu) variant has been reported in the published literature in individuals with breast (PMIDs: 30982232 (2019), 32019277 (2020)), colorectal (PMIDs: 28874130 (2017), 28932927 (2018), 29575718 (2018)), pancreatic (PMID: 32980694 (2020)), and bile duct cancer (PMID: 31666926 (2019)). The frequency of this variant in the general population, 0.00049 (9/18392 chromosomes in East Asian subpopulation (Genome Aggregation Database, 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000491197	SCV000905458	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 1258 of the MSH6 protein. Computational prediction 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 reported for this variant. This variant has been observed in individuals affected with Lynch syndrome (PMID: 28874130, 28932927, 29575718, 31386297), pancreatic cancer (PMID: 32980694), and breast or ovarian cancer (PMID: 30982232, 32019277). One individual affected with Lynch syndrome was reported to have an unspecified pathogenic co-variant and lacked phenotypes expected for biallelic constitutional mismatch repair deficiency (PMID: 29575718), while another showed microsatellite stability and presence of mismatch repair proteins by immunohistochemistry (PMID: 31386297). This variant has been identified in 10/251214 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been reported in healthy individuals (PMID: 32980694). 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	RCV000479785	SCV001360534	uncertain significance	not specified	2019-07-26	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3772C>G (p.Gln1258Glu) results in a conservative amino acid change located in the C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251214 control chromosomes, predominantly at a frequency of 0.00049 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3772C>G has been reported in the literature in individuals affected with Lynch Syndrome (Rossi_2017, Soares_2018, Schneider_2018) and familial breast cancer (Wang_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant (after 2014) and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000479785	SCV002552364	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998730	SCV004835135	uncertain significance	Lynch syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 1258 of the MSH6 protein. Computational prediction 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 reported for this variant. This variant has been observed in individuals affected with Lynch syndrome (PMID: 28874130, 28932927, 29575718, 31386297), pancreatic cancer (PMID: 32980694), and breast or ovarian cancer (PMID: 30982232, 32019277). One individual affected with Lynch syndrome was reported to have an unspecified pathogenic co-variant and lacked phenotypes expected for biallelic constitutional mismatch repair deficiency (PMID: 29575718), while another showed microsatellite stability and presence of mismatch repair proteins by immunohistochemistry (PMID: 31386297). This variant has been identified in 10/251214 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been reported in healthy individuals (PMID: 32980694). 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.
Baylor Genetics	RCV004567714	SCV005054951	uncertain significance	Endometrial carcinoma	2024-01-27	criteria provided, single submitter	clinical testing