Submissions for variant NM_000179.3(MSH6):c.1739C>T (p.Ser580Leu)

gnomAD frequency: 0.00002  dbSNP: rs41295270

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131189	SCV000186139	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-18	criteria provided, single submitter	clinical testing	The p.S580L variant (also known as c.1739C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1739. The serine at codon 580 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in individuals diagnosed with colorectal cancer (Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74; Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806; Fummey E et al. J Med Genet, 2024 Aug;61:861-869), breast cancer (Bhai P et al. Front Genet, 2021 Jul;12:698595; Dorling et al. N Engl J Med 2021 02;384:428-439). It has also been reported in unaffected control individuals (Dorling et al. N Engl J Med 2021 02;384:428-439; Mizukami K et al. EBioMedicine, 2020 Oct;60:103033). This variant has also been reported in a HNPCC-like family; however, no other clinical information was provided (Devlin LA et al. Ulster Med J. 2008 Jan;77:25-30). This variant was also reported in an individual with colorectal cancer whose tumor demonstrated loss of expression of MLH1/PMS2 on IHC and intact MSH2/MSH6, in addition to MLH1 promoter hypermethylation and BRAF V600E. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524119	SCV000254280	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131189	SCV000537562	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 580 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 two individuals affected with Lynch syndrome-associated cancer, in which one tumor was found to have stable microsatellite markers and had detectable DNA mismatch repair proteins (PMID: 18033691, 18269114). This variant also has been reported in a pancreatic cancer case-control study in 2 unaffected controls and absent in 1005 cancer cases (PMID: 32980694) and a breast cancer case-control study in 5 breast cancer cases and 8 unaffected controls (PMID: 33471991). This variant has been identified in 16/281632 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.
GeneDx	RCV000485534	SCV000565217	uncertain significance	not provided	2024-06-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced MMR activity compared to wild type (PMID: 31965077); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal cancer, including some with tumor studies that were not consistent with MSH6-related Lynch syndrome, and in individuals with breast cancer, at least one of whom was also positive for a pathogenic BRCA2 variant (PMID: 18033691, 18269114, 29596542, 30267214, 33471991, 34326862); This variant is associated with the following publications: (PMID: 24362816, 26333163, 23621914, 22949387, doi:10.5923/j.bioinformatics.20160602.03, 27527004, 29596542, 34288098, 30267214, 34687117, 31391288, 32980694, 33471991, 18269114, 19389263, 18033691, 17531815, 21120944, 36243179, 34326862, 31965077)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485534	SCV002046203	uncertain significance	not provided	2022-11-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000098 (3/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in individual with Lynch syndrome (PMID: 18269114 (2008)), colorectal cancer (PMID: 18033691 (2008)), and breast cancer (PMID: 33471991 (2021)). The variant has also been reported in unaffected individuals (PMID: 33471991 (2021)). An invitro functional study has reported that this variant reduced mismatch repair efficiency (PMID: 31965077 (2020)). 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.
Genetic Services Laboratory, University of Chicago	RCV001818236	SCV002064673	uncertain significance	not specified	2019-07-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131189	SCV002535655	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818236	SCV002765955	uncertain significance	not specified	2022-11-21	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1739C>T (p.Ser580Leu) results in a non-conservative amino acid change located in the connector domain (IPR007860) 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 6e-05 in 297806 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (6e-05 vs 0.00014), allowing no conclusion about variant significance. c.1739C>T has been reported in the literature in at least one individual with an HNPCC-like classification not meeting Amsterdam criteria, in an individual affected with colorectal cancer at <55 years of age, but with a microsatellite stable tumor which was positive for MSH6, MSH2 and MLS1 by immunohistochemistry, and as a VUS in an individual affected with a cancer within the Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch syndrome spectrum (e.g. Devlin_2008, Barnetson_2008, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with HNPCC/Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Drost_2020). The variant was found to have a MMR activity 10-30% of normal, determined by CIMRA assay. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498356	SCV002779523	uncertain significance	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-03-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000485534	SCV002822647	likely pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466936	SCV004195704	uncertain significance	Endometrial carcinoma	2024-03-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004019093	SCV004931779	likely benign	Lynch syndrome 5	2024-03-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005357440	SCV005917034	uncertain significance	Lynch syndrome	2021-07-15	criteria provided, single submitter	clinical testing