Submissions for variant NM_000179.3(MSH6):c.1844G>T (p.Cys615Phe)

dbSNP: rs730881793

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165560	SCV000216293	likely benign	Hereditary cancer-predisposing syndrome	2023-06-15	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	RCV000168072	SCV000218726	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000479956	SCV000565218	uncertain significance	not provided	2023-03-20	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 cancer or other advanced cancer (Mandelker et al., 2017; Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 28873162, 28002797, 28135145, 17531815, 21120944)
Color Diagnostics, LLC DBA Color Health	RCV000165560	SCV000690226	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 615 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 reported in two individuals affected with colorectal cancer (PMID: 28135145) and in an individual affected with an unspecified advanced cancer (PMID: 28873162). This variant has been identified in 2/31400 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	RCV000479956	SCV002046208	uncertain significance	not provided	2023-05-26	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an affected individual with colorectal cancer (PMID: 28135145 (2017)) and in a patient cohort with advanced cancer (PMID: 28873162 (2017)). The frequency of this variant in the general population, 0.000064 (2/31400 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000165560	SCV002535666	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-15	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469035	SCV002765954	uncertain significance	not specified	2023-11-08	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1844G>T (p.Cys615Phe) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250636 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1844G>T has been reported in the literature in individuals affected with Colorectal Cancer without strong evidence of causality (e.g., Yurgelun_2017). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 28135145). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n = 5; likely benign, n = 1; benign, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003462180	SCV004195608	uncertain significance	Endometrial carcinoma	2023-08-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995427	SCV004840240	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 615 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 reported in two individuals affected with colorectal cancer (PMID: 28135145) and in an individual affected with an unspecified advanced cancer (PMID: 28873162). This variant has been identified in 2/31400 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.
Genetic Services Laboratory, University of Chicago	RCV002469035	SCV003839752	uncertain significance	not specified	2022-06-13	no assertion criteria provided	clinical testing	DNA sequence analysis of the MSH6 gene demonstrated a sequence change, c.1844G>T, in exon 4 that results in an amino acid change, p.Cys615Phe. This sequence change has been identified in two individuals with colorectal cancer (PMID: 28135145). This sequence change has been described in the gnomAD database with a frequency of 0.0064% in the overall population (dbSNP rs730881793). The p.Cys615Phe change affects a poorly conserved amino acid residue located in a domain of the MSH6 protein that is known to be functional. The p.Cys615Phe substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Cys615Phe change remains unknown at this time. Heterozygous pathogenic variants in MSH6 are associated with Lynch syndrome [OMIM# 614350], which is associated with an increased risk of certain cancers, particularly colon and endometrial cancers. Hematological malignancies have been reported in some cases of Lynch syndrome however the exact risk is not well defined (PMID: 23730225). Homozygous or compound heterozygous pathogenic variants in MSH6 lead to a mismatch repair deficiency which is a rare childhood cancer predisposition syndrome with 4 main tumor types: hematologic malignancies, brain/central nervous system tumors, colorectal tumors and multiple intestinal polyps, and other malignancies including embryonic tumors and rhabdomyosarcoma [OMIM# 276300] (PMIDs: 19493351).