Submissions for variant NM_000179.3(MSH6):c.3425C>T (p.Thr1142Met)

gnomAD frequency: 0.00005  dbSNP: rs267608089

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656899	SCV000149324	uncertain significance	not provided	2023-10-04	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; Observed in individuals with polyps or history suggestive of hereditary breast and ovarian cancer syndrome (Perez-Cabornero et al., 2013; Castera et al., 2014); Published functional studies demonstrate proficient mismatch repair activity (Houlleberghs et al., 2017); This variant is associated with the following publications: (PMID: 26333163, 27632392, 23621914, 23523604, 19250818, 23588873, 24549055, n/a, 12019211, 21120944, 28531214, 33471991, 32885271)
Invitae	RCV000524175	SCV000166230	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115415	SCV000186590	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-30	criteria provided, single submitter	clinical testing	The p.T1142M variant (also known as c.3425C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3425. The threonine at codon 1142 is replaced by methionine, an amino acid with similar properties. This variant was reported in a Spanish family meeting Amsterdam criteria and segregated with disease in 2/2 affected relatives; however, tumor testing in this family demonstrated microsatellite stability and normal staining on IHC (Perez-Cabornero L et al. Eur. J. Cancer. 2009 May;45:1485-93; Perez-Cabornero L et al. J Mol Diagn. 2013 May;15:380-90). This alteration was reported in a cohort of suspected hereditary breast and ovarian cancer patients who underwent multi-gene panel testing (Castéra L et al. Eur. J. Hum. Genet., 2014 Nov;22:1305-13). This variant was also observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879), and was reported in 3/60,466 breast cancer cases and in 4/53,461 controls in another study (Dorling et al. N Engl J Med. 2021 02;384:428-439). In a functional study that utilized a genetic screening method to test mismatch repair activity in murine embryonic stem cells, p.T1142M did not demonstrate attenuated mismatch repair (Houlleberghs H et al. PLoS Genet., 2017 May;13:e1006765). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212683	SCV000539707	uncertain significance	not specified	2016-06-16	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 4 VUS (including expert panel - no new evidence since expert classification)
Color Diagnostics, LLC DBA Color Health	RCV000115415	SCV000685399	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1142 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). A functional assay to detect DNA mismatch repair (MMR) deficiency in MSH6 deficient mouse embryonic stem cells found that the variant protein is likely MMR proficient (PMID: 28531214). This variant has been reported in individuals affected with Lynch syndrome (PMID: 19250818, 23523604), and an individual suspected to be affected with hereditary breast and ovarian cancer (PMID: 24549055). This variant has been identified in 7/282732 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	RCV000656899	SCV000888273	uncertain significance	not provided	2022-05-26	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000031 (4/129104 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with personal or family history of breast/ovarian cancer, and in two family members affected with colon polyps (PMID: 24549055 (2014), 23523604 (2013)). In vitro functional study evaluating the function of the variant in response to a DNA-damaging agent indicated that this variant may not be pathogenic (PMID: 28531214 (2017)). Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212683	SCV001426992	uncertain significance	not specified	2021-09-11	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3425C>T (p.Thr1142Met) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain 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 2.4e-05 in 252032 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3425C>T has been reported in the literature in individuals affected with Lynch Syndrome or HBOC (example, Perez-Cabornero_2013, Castera_2014). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on mismatch repair (MMR) activity (Houlleberghs_2017). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656899	SCV002010093	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115415	SCV002528022	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288562	SCV002579167	uncertain significance	Lynch syndrome 5	2022-06-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000656899	SCV003808966	uncertain significance	not provided	2022-12-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460683	SCV004197677	uncertain significance	Endometrial carcinoma	2023-10-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997089	SCV004835066	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1142 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). A functional assay to detect DNA mismatch repair (MMR) deficiency in MSH6 deficient mouse embryonic stem cells found that the variant protein is likely MMR proficient (PMID: 28531214). This variant has been reported in individuals affected with Lynch syndrome (PMID: 19250818, 23523604, Goverde 2018) and an individual suspected to be affected with hereditary breast and ovarian cancer (PMID: 24549055). This variant has been identified in 7/282732 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357449	SCV001552926	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Thr1142Met variant was identified in 3 of 1454 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer/ovarian cancer, Lynch Syndrome, and polyps (Castera 2014, Perez-Cabornero 2009, Perez-Cabornero 2013). The variant was also identified in the following databases: dbSNP (ID: rs267608089) as "With Uncertain significance allele", ClinVar (5x, uncertain significance), Clinvitae (3x, uncertain significance), Cosmic (2x, confirmed somatic, in a carcinoma of the liver), Insight Colon Cancer Gene Variant Database (1x, uncertain significance), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was not identified in MutDB, UMD-LSDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 7 of 277124 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). A functional study used an oligonucleotide directed mutagenesis screen in mouse embryonic stem cells to determine pathogenicity for MSH6 variants (Houlleberghs 2017). The c.3425C>T variant was classified as "not pathogenic" by this method. The p.Thr1142 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is also not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.