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

gnomAD frequency: 0.00002  dbSNP: rs63750836

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131709	SCV000186747	likely benign	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV001082428	SCV000259281	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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	2022-11-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in individuals with a personal or family history of pancreatic cancer, rhabdomyosarcoma, a microsatellite stable (MSS) colon tumor, and/or other cancers (Chan et al., 1999; Yan et al., 2007; Chan et al., 2017; Young et al., 2018); Published functional studies demonstrate no damaging effect: subcellular localization and mismatch repair activity similar to wild type (Belvederesi et al., 2012; Drost et al., 2020); This variant is associated with the following publications: (PMID: 23621914, 17854147, 26333163, 10413423, 22851212, 29945567, 28878254, 31965077, 17531815, 21120944)
Color Diagnostics, LLC DBA Color Health	RCV000131709	SCV000685455	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-08	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 individuals affected with sporadic sarcomas, pancreatic cancer, or breast cancer (PMID: 28878254, 29945567, 32068069). 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	Lynch syndrome 5	2017-04-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759868	SCV000889498	likely benign	not provided	2023-06-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000662523	SCV001135850	uncertain significance	Lynch syndrome 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.
Myriad Genetics, Inc.	RCV000662523	SCV004018975	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].
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003448259	SCV004176400	uncertain significance	Endometrial carcinoma	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.3851C>T (p.Thr1284Met) variant in MSH6 gene has been reported previously in individuals in heterozygous state with MSH6-related susceptiblity to cancer (Yan et al. 2007; Chan et al. 2017; Young et al. 2018). The p.Thr1284Met variant is reported with an allele frequency of 0.02% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Benign / Uncertain Significance (multiple submissions). The amino acid change p.Thr1284Met in MSH6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 1284 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492403	SCV004239321	uncertain significance	Breast and/or ovarian cancer	2022-08-29	criteria provided, single submitter	clinical testing
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.