Submissions for variant NM_000179.3(MSH6):c.1299T>G (p.Tyr433Ter)

dbSNP: rs267608055

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491745	SCV000580275	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	The p.Y433* pathogenic mutation (also known as c.1299T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 1299. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223369	SCV001395514	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 428379). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr433*) 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).
GeneDx	RCV001786392	SCV002028687	pathogenic	not provided	2021-11-23	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 (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18269114, 24362816)
Myriad Genetics, Inc.	RCV003449318	SCV004188304	pathogenic	Lynch syndrome 5	2023-08-11	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	RCV003464055	SCV004196380	likely pathogenic	Endometrial carcinoma	2021-04-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000502404	SCV000592583	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Tyr433X variant was not identified in the literature nor was it identified in the in dbSNP, (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database, COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight COGR database, and UMD. The p.Tyr433X variant leads to a premature stop codon at position 433, 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.