Submissions for variant NM_000179.3(MSH6):c.3674C>T (p.Thr1225Met)

gnomAD frequency: 0.00011  dbSNP: rs63750370

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212686	SCV000211324	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with colorectal or endometrial cancer, including some with tumor studies demonstrating results inconsistent with pathogenic variants in this gene (Wijnen et al., 1999; Hampel et al., 2006; Lagerstedt Robinson et al., 2007; Nilbert et al., 2009; Drost et al., 2012; Houlleberghs et al., 2017); Published functional assays demonstrate mismatch repair activity comparable to wild type (Drost et al., 2012; Houlleberghs et al., 2017); This variant is associated with the following publications: (PMID: 27601186, 10508506, 22102614, 17312306, 18566915, 16885385, 23621914, 26333163, 33726816, 12019211, 17531815, 21120944, 28531214, 34598035, 30982232, 32091409, 26689913, 24448499, 32547938, 29945567)
Ambry Genetics	RCV000160696	SCV000212834	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	The p.T1225M variant (also known as c.3674C>T), located in coding exon 8 of the MSH6 gene, results from a C to T substitution at nucleotide position 3674. The threonine at codon 1225 is replaced by methionine, an amino acid with similar properties. This variant has been identified in multiple high-risk colorectal/endometrial cancer patients (Wijnen J et al. Nat. Genet., 1999 Oct;23:142-4; Hampel H et al. Cancer Res., 2006 Aug;66:7810-7; Lagerstedt Robinson K et al. J. Natl. Cancer Inst., 2007 Feb;99:291-9; Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83). However, functional analyses have demonstrated near-wild-type mismatch repair activity for the p.T1225M allele (Drost M et al. Hum Mutat., 2012 Mar;33:488-94; Houlleberghs H et al. PLoS Genet, 2017 May;13:e1006765). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000524182	SCV000254319	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000410774	SCV000489095	uncertain significance	Lynch syndrome 5	2016-08-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160696	SCV000685429	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1225 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). Functional studies have shown that this variant does not affect MSH6 protein mismatch repair function or result in DNA damage resistance (PMID: 22102614, 28531214). This variant has been reported in individuals affected with Lynch syndrome (PMID: 10508506, 18566915, 27601186), endometrial cancer (PMID: 16885385), head and neck squamous cell carcinoma (PMID: 34598035) and breast cancer (PMID: 30982232, 32547938). This variant has also been observed in an individual affected with colorectal cancer, whose tumor showed microsatellite stability and normal MSH6 protein expression (PMID: 17312306). This variant has been identified in 22/282650 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	RCV000780485	SCV000917775	uncertain significance	not specified	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3674C>T (p.Thr1225Met) results in a non-conservative amino acid change located in the C-terminal region (IPR000432) and ATPase domain (Houlleberghs_MSH6_PLOS Genetics_2017) 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 7.6e-05 in 251248 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is slightly less than the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting that the variant might be a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.3674C>T, has been reported in the literature in individuals affected with Lynch Syndrome, colorectal cancer or other cancers, without strong evidence for causality (examples: Wijnen 1999, Hampel_2006, Nilbert_2009, Lagerstedt-Robinson_2007 and 2016, Bhai_2021, Djursby_2022, Fanale_2022, Okawa_2023). An endometrial tumor sample from one patient showed microsatellite instability but showed retention of MSH6 and MSH2 and loss of MLH1/PMS2 with MLH1 promoter hypermethylation (Hampel_2006). Thus these data do not allow any conclusion about variant significance. At least two publications reported experimental evidence evaluating an impact on protein function, and showed no damaging effect of this variant (Drost 2011, Houlleberghs 2017). The following publications have been ascertained in the context of this evaluation (PMID: 22102614, 16885385, 28531214, 27601186, 17312306, 18566915, 26333163, 30982232, 10508506, 29945567, 34326862, 35904628, 35223509, 36243179). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212686	SCV001134438	uncertain significance	not provided	2020-06-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000780485	SCV002065589	uncertain significance	not specified	2017-12-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780485	SCV002552358	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410774	SCV004019029	likely benign	Lynch syndrome 5	2023-03-29	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: 25085752].
Baylor Genetics	RCV003460688	SCV004197674	uncertain significance	Endometrial carcinoma	2023-10-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997095	SCV004835111	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1225 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). Functional studies have shown that this variant does not affect MSH6 protein mismatch repair function or result in DNA damage resistance (PMID: 22102614, 28531214). This variant has been reported in individuals affected with Lynch syndrome (PMID: 10508506, 18566915, 27601186), endometrial cancer (PMID: 16885385), head and neck squamous cell carcinoma (PMID: 34598035) and breast cancer (PMID: 30982232, 32547938). This variant has also been observed in an individual affected with colorectal cancer, whose tumor showed microsatellite stability and normal MSH6 protein expression (PMID: 17312306). This variant has been identified in 22/282650 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	RCV001354592	SCV001549242	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Thr1225Met variant was identified in 8 of 11332 proband chromosomes (frequency: 0.0007) from individuals or families with HNPCC, Lynch syndrome, endometrial cancer, or prostate adenocarcinoma (Hampel 2006, Lagerstedt-Robinson 2007, Lagerstedt-Robinson 2016, Lu 2015, Nilbert 2009). The variant was also identified in dbSNP (ID: rs63750370) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and three other submitters), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (2x). The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, or the Zhejiang University database. The variant was identified in control databases in 24 of 276978 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 19 of 126534 chromosomes (freq: 0.0002), East Asian in 1 of 18864 chromosomes (freq: 0.00005), Finnish in 1 of 25784 chromosomes (freq: 0.00004), and South Asian in 3 of 30782 chromosomes (freq: 0.0001); it was not observed in the African, Other, Latino, and Ashkenazi Jewish, populations. The p.Thr1225 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
Clinical Genetics, Academic Medical Center	RCV000212686	SCV001919371	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212686	SCV001963116	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153344	SCV003843674	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing