ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3851C>T (p.Thr1284Met) (rs63750836)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131709 SCV000186747 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-13 criteria provided, single submitter clinical testing The p.T1284M variant (also known as c.3851C>T), located in coding exon 9 of the MSH6 gene, results from a C to T substitution at nucleotide position 3851. The threonine at codon 1284 is replaced by methionine, an amino acid with similar properties. In one study of Chinese colorectal cancer patients, this alteration was detected in a 29-year-old male whose colon tumor was microsatellite stable (Chan TL et al. J Natl Cancer Inst. 1999 Jul 21;91(14):1221-6). In another study of Chinese HNPCC patients, this alteration was detected in an individual fulfilling Bethesda criteria who had cancer of the descending colon at 51 years and metachronous endometrial cancer (Yan SY et al. World J Gastroenterol 2007 October 7; 13(37): 5021-5024). This alteration has been classified as a variant of uncertain significance by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). 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.
Invitae RCV001082428 SCV000259281 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000454725 SCV000539710 uncertain significance not specified 2016-06-23 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: 2 VUS (including expert panel, no new evidence since expert classification)
GeneDx RCV000759868 SCV000565237 uncertain significance not provided 2018-11-05 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3851C>T at the cDNA level, p.Thr1284Met (T1284M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been reported in an individual with a microsatellite stable (MSS) colon tumor, in an individual with pancreatic cancer, and in another individual whose personal and/or family history was suggestive of Lynch syndrome (Chan 1999, Yan 2007, Young 2018). A subcellular localization assay demonstrated no measurable difference between MSH6 Thr1284Met and wild type, suggesting this variant does not disrupt nuclear localization (Belvederesi 2012). MSH6 Thr1284Met was observed at an allele frequency of 0.11% (35/30,778) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MSH6 Thr1284Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000131709 SCV000685455 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-20 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 1284 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 study reported that this variant has normal nuclear localization in transfected ex vivo cells (PMID: 22851212). This variant has been observed in an individual affected with microsatellite stable colorectal cancer and another individual affected with colorectal and endometrial cancer whose tumor showed the loss of MSH6 by immunohistochemistry (PMID: 10413423, 17854147, 18067074; InSiGHT database). This variant also has been observed in one individual each affected with sporadic sarcomas and pancreatic cancer (PMID: 28878254, 29945567). This variant has been identified in 50/282196 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.
Counsyl RCV000662523 SCV000785081 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759868 SCV000889498 likely benign not provided 2018-12-21 criteria provided, single submitter clinical testing
Mendelics RCV000662523 SCV001135850 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000454725 SCV001363791 likely benign not specified 2019-11-25 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3851C>T (p.Thr1284Met) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) 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 0.00019 in 251304 control chromosomes, predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3851C>T has been reported in the literature in individuals affected with Lynch Syndrome, sporadic sarcoma, or pancreatic cancer (Chan_1999, Yan_2007, Belvederesi_2012, Chan_2017, Young_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (6x VUS, 1x likely benign). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357732 SCV001553288 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Thr1284Met variant was identified in 2 of 312 proband chromosomes (frequency: 0.006) from individuals or families with colorectal cancer (Chan 1999, Yan 2007). The variant was also identified in the following databases: dbSNP (ID: rs63750836) as With Uncertain significance allele, ClinVar (classified as uncertain significance by InSight, Ambry Genetics, GenDx; classified as likely benign by Ivitae), Clinvitae (classified as uncertain significance by ClinVar), MutDB (unclassified), Insight Colon Cancer Gene Variant Database (4X class3), Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (4X). The variant was not identified in Cosmic, UMD-LSDB, databases. The variant was identified in control databases in 50 of 276776 chromosomes at a frequency of 0.000181 (Genome Aggregation Consortium Feb 27, 2017). The sub-cellular localization analysis of this variant suggested a proper MSH6 nuclear import (Belvederesi 2012). The p.Thr1284 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the DNA mismatch repair protein MutS, C-terminal P-loop containing nucleoside triphosphate hydrolase DNA mismatch repair protein Msh6 functional domains. 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.

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