Submissions for variant NM_000179.3(MSH6):c.3477C>A (p.Tyr1159Ter)

dbSNP: rs398123231

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078315	SCV000110159	pathogenic	not provided	2013-06-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456684	SCV000551165	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-09-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1159*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome-associated cancers (PMID: 21642682, 21868491). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 92577). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491158	SCV000580185	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-19	criteria provided, single submitter	clinical testing	The p.Y1159* pathogenic mutation (also known as c.3477C>A), located in coding exon 6 of the MSH6 gene, results from a C to A substitution at nucleotide position 3477. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This mutation was identified in a single French family suspected of Lynch syndrome in one study (Bonadona V et al. JAMA 2011 Jun;305:2304-10). 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	RCV002265599	SCV000919761	pathogenic	Hereditary nonpolyposis colon cancer	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3477C>A (p.Tyr1159X) 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 was absent in 251396 control chromosomes. c.3477C>A has been reported in the literature in individuals affected with Lynch Syndrome (example, Bonadona_2011, Perez-Carbonell_2011, Marignol_2008, Rey_2017, Ferrer-Avargues_2021, Post_2021). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491158	SCV001340971	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 6 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 not been identified 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.
GeneDx	RCV000078315	SCV002102639	pathogenic	not provided	2024-03-12	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal and/or family history consistent with pathogenic variants in this gene (PMID: 21642682, 21868491, 33693762); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21642682, 21868491, 28502729, 32719484, 33630411, 36974006, 33693762)
Genetics and Molecular Pathology, SA Pathology	RCV002272057	SCV002556696	likely pathogenic	Lynch syndrome	2021-07-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003453005	SCV004188308	pathogenic	Lynch syndrome 5	2023-08-23	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	RCV003466970	SCV004195571	pathogenic	Endometrial carcinoma	2023-08-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000078315	SCV000257257	pathogenic	not provided		no assertion criteria provided	research
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249964	SCV001423978	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354656	SCV001549322	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Tyr1159* variant was identified in 2 of 5260 proband chromosomes (frequency: 0.0004) from individuals or families with colon cancer (Bonadona 2011, Perez-Cabornell 2011). The variant was also identified in dbSNP (ID: rs398123231) as “With Pathogenic, Uncertain significance allele"), ClinVar (classified as pathogenic by Invitae, Ambry Genetics, and two other clinical laboratories), UMD-LSDB (12x as causal), and in Insight InSiGHT Hereditary Tumors databases. The variant was not identified in the COGR, Cosmic, MutDB, Zhejiang University Database, and or Mismatch Repair Genes Variant databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Tyr1159* variant leads to a premature stop codon at position 1159, 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.