Submissions for variant NM_000179.3(MSH6):c.2764C>T (p.Arg922Ter)

dbSNP: rs587779246

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074779	SCV000107989	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000491845	SCV000580132	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-05	criteria provided, single submitter	clinical testing	The p.R922* pathogenic mutation (also known as c.2764C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2764. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been identified in multiple Lynch syndrome families (Bonadona V et al. JAMA 2011 Jun;305(22):2304-10; Sjursen W et al. Mol. Genet. Genomic Med. 2016 Jan 11;4(2):223-31; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Post CCB et al. J Natl Cancer Inst, 2021 Mar). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281907	SCV000695829	pathogenic	Hereditary nonpolyposis colon cancer	2022-07-25	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2764C>T (p.Arg922X) 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. The variant allele was found at a frequency of 4e-06 in 250966 control chromosomes (gnomAD). c.2764C>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer, colorectal cancer, and Lynch syndrome (examples: Bonadona_2011, Ward_2013 and Sjursen_2015). These data indicate that the variant is very likely to be associated with disease. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056241	SCV001220673	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-09-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg922*) 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 (rs587779246, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with colorectal cancer or breast cancer and Lynch syndrome (PMID: 21642682, 23733757, 28724667). ClinVar contains an entry for this variant (Variation ID: 89314). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491845	SCV001341248	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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 identified in 1/250966 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262897	SCV001440933	pathogenic	Lynch syndrome 5	2019-01-01	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000491845	SCV001950433	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-09	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267828	SCV002552313	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV001262897	SCV002556671	pathogenic	Lynch syndrome 5	2022-05-13	criteria provided, single submitter	clinical testing	The MSH6 c.2764C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2)
GeneDx	RCV002267828	SCV003798794	pathogenic	not provided	2023-01-26	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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Bonadona et al., 2011; Ward et al., 2013; Sjursen et al., 2016; Jiang et al., 2019); 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: 32980694, 31830689, 29922827, 23733757, 27064304, 21642682, 29489754, 28724667, 30521064, 31491536, 26374070, 23700467, 33693762)
Revvity Omics, Revvity	RCV002267828	SCV003820134	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001262897	SCV004188189	pathogenic	Lynch syndrome 5	2023-08-18	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	RCV003460672	SCV004196369	pathogenic	Endometrial carcinoma	2021-06-29	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357595	SCV001553108	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Arg922* variant was identified in 5 of 2856 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome or colorectal cancer (Bonadona 2011, Han 2013, Sjursen 2016). The variant was also identified in the following databases: dbSNP (ID: rs587779246) as "With Pathogenic allele", ClinVar (classified as pathogenic by InSight, Ambry Genetics, and one other clinical laboratory), Cosmic (3x in breast or large intestine tissue), UMD-LSDB (4x causal), and the Insight Hereditary Tumors database. The variant was not identified in the COGR, Zhejiang University Database, or Mismatch Repair Genes Variant database. The variant was identified in control databases in 1 of 245720 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 1 of 30774 chromosomes (freq: 0.000032); it was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The c.2764C>T variant leads to a premature stop codon at position 922, 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 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.
Laboratory for Genotyping Development, RIKEN	RCV003162472	SCV002758544	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research