Submissions for variant NM_000179.3(MSH6):c.2194C>T (p.Arg732Ter)

dbSNP: rs63751127

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074726	SCV000107934	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000132226	SCV000187309	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	clinical testing	The p.R732* pathogenic mutation (also known as c.2194C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2194. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in multiple individuals satisfying HNPCC/Lynch syndrome clinical criteria with tumors showing microsatellite instability and absence of MSH6 staining on IHC (Plaschke J et al. J. Clin Oncol. 2004;22:4486-4494; Steinke V et al. Eur J Hum Genet. 2008 May;16(5):587-92). This alteration has also been reported in individuals diagnosed with breast, ovarian, pancreatic, prostate and uterine cancers (Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Dondi G et al. Int J Mol Sci, 2020 Sep;21:; Mannucci A et al. Eur J Gastroenterol Hepatol, 2020 03;32:345-349; Wu Y et al. Eur Urol Oncol, 2020 04;3:224-230). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000212661	SCV000211293	pathogenic	not provided	2022-06-11	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 20028993, 20924129, 15483016, 25525159, 27601186, 26681312, 24728189, 27153395, 28874130, 33087929, 30521064, 30787465, 31851094, 32294063, 31948886, 18301448)
Invitae	RCV000524134	SCV000253776	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg732*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs63751127, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and Lynch syndrome (PMID: 15483016, 18301448, 20028993, 24728189). ClinVar contains an entry for this variant (Variation ID: 89262). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074726	SCV000711432	pathogenic	Lynch syndrome	2023-09-13	criteria provided, single submitter	clinical testing	The p.Arg732X variant in MSH6 has been reported in at least 5 individuals with hereditary non-polyposis colorectal cancer (HNPCC) and related tumors (Plaschke 2004 PMID: 15483016, Steinke 2008 PMID: 18301448, Baglietto 2010 PMID: 20028993, Giraldez 2010 PMID: 20924129, Song 2014 PMID: 24728189). This variant has also been identified in 0.001% (1/68036) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 732, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism for Lynch syndrome. Moreover, this variant was classified as pathogenic on Sept. 05, 2013 by the ClinGen approved InSiGHT expert panel (Variation ID: 89262). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PS4_Moderate.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212661	SCV000889471	pathogenic	not provided	2018-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132226	SCV000905454	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 15483016, 18301448, 20028993, 27601186, 28874130) and breast cancer (PMID: 33471991). This variant has been identified in 1/250888 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281906	SCV000919757	pathogenic	Hereditary nonpolyposis colon cancer	2022-08-29	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2194C>T (p.Arg732X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and also observed in the HGMD database. The variant allele was found at a frequency of 4e-06 in 250888 control chromosomes. c.2194C>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Example: Susswein_2015, Rossi_2017, Baglietto_2010, Song_2014, Jiang_2019 etc.). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212661	SCV002552304	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000212661	SCV003820145	pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450944	SCV004188231	pathogenic	Lynch syndrome 5	2023-08-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV003466942	SCV004195662	pathogenic	Endometrial carcinoma	2023-07-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074726	SCV000592600	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The p.Arg732X variant was identified in 2 of 1692 proband chromosomes (frequency: 0.001) from individuals or families with early-onset colorectal cancer or Lynch syndrome (Giráldez 2010, Plaschke 2004). The tumours from the positive probands in these studies showed loss of MSH6 protein by immunohistochemistry; one tumour also showed high microsatellite instability. The variant was also identified in dbSNP (ID: rs63751127) “With Pathogenic allele”, GeneInsight COGR database (classified as pathogenic by a clinical laboratory), HGMD, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, UMD (2X as a “causal” variant), and in the ClinVar database (classified as a pathogenic by all three submitters: InSiGHT, Ambry Genetics, and GeneDx). The p.Arg732X variant leads to a premature stop codon at position 732, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.