Submissions for variant NM_000179.3(MSH6):c.2780T>C (p.Ile927Thr)

gnomAD frequency: 0.00003  dbSNP: rs587779926

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587183	SCV000149304	uncertain significance	not provided	2023-08-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 24100870, 26689913, 21120944, 17531815, 32068069, 25186627, 32826389, 36243179, 35449176)
Ambry Genetics	RCV000115395	SCV000215177	likely benign	Hereditary cancer-predisposing syndrome	2018-11-26	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	RCV000206053	SCV000260782	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 927 of the MSH6 protein (p.Ile927Thr). This variant is present in population databases (rs587779926, gnomAD 0.01%). This missense change has been observed in individual(s) with MSH6-related conditions (PMID: 24100870, 26689913, 32826389, 34326862, 35449176, 36243179). This variant is also known as p.I625T. ClinVar contains an entry for this variant (Variation ID: 127574). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587183	SCV000601542	uncertain significance	not provided	2023-08-18	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in cases of colorectal cancer (PMID: 24100870 (2013), breast cancer (PMIDs: 32068069 (2020), 25186627 (2015)), and low grade glioma (PMID: 26689913 (2015)). The frequency of this variant in the general population, 0.000018 (5/282352 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000115395	SCV000690290	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 927 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 an individual affected with colorectal cancer at age 86 with no family history of colorectal cancer (PMID: 24100870). Her tumor sample showed high microsatellite instability and lack of MLH1 and PMS2 protein expression. This variant has been observed in an individual with low grade glioma (PMID: 26689913) and in 7 unaffected control individuals in a pancreatic cancer case-control study (PMID: 32980694). This variant has also been identified in 5/282352 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	RCV000212671	SCV000695830	uncertain significance	not specified	2022-05-08	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2780T>C (p.Ile927Thr) 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 1.6e-05 in 250950 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2780T>C has been reported in the literature in at least one colorectal cancer patient (immunohistochemistry on the patient's tumor sample displayed lack of MLH1/PMS2 staining; MLH1 promoter hypermethylation was noted) (Terui_2013). In addition, the variant has been reported as a VUS in settings of multigene panel testing among individuals affected with breast cancer and in The Cancer Genome Atlas (TGCA) cohort (low grade glioma) (e.g. Lu_2015, Tung_2015, Kwong_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. At-least one co-occurrences with another pathogenic variant(s) has been observed at our laboratory (CHEK2 c.1100delC, p.Thr367MetfsX15), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance, while one ClinVar submitter (evaluation after 2014) cites the variant as likely benign reporting it seen in trans with a mutation or in homozygous state in individual without severe disease for the gene (SCV000215177.4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253566	SCV001429352	uncertain significance	Lynch syndrome 5	2019-09-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212671	SCV002552314	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460815	SCV004197660	uncertain significance	Endometrial carcinoma	2023-10-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997243	SCV004836276	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 927 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 an individual affected with colorectal cancer at age 86 with no family history of colorectal cancer (PMID: 24100870). Her tumor sample showed high microsatellite instability and lack of MLH1 and PMS2 protein expression. This variant has been observed in an individual with low grade glioma (PMID: 26689913) and in 7 unaffected control individuals in a pancreatic cancer case-control study (PMID: 32980694). This variant has also been identified in 5/282352 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.