Submissions for variant NM_000179.3(MSH6):c.1883G>A (p.Trp628Ter)

dbSNP: rs863225401

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV003454526	SCV004185787	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.
GeneDx	RCV000202222	SCV005332993	pathogenic	not provided	2024-03-28	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 individuals with colorectal cancer (PMID: 28975465); Observed as apparently homozygous in two pediatric siblings, one with glioblastoma and the other with T-cell lymphoma (PMID: 30104292); 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: 28975465, 37306523, 30104292)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003454526	SCV005442269	pathogenic	Lynch syndrome 5	2024-12-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202222	SCV000257217	likely pathogenic	not provided		no assertion criteria provided	research
True Health Diagnostics	RCV000664275	SCV000788044	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354409	SCV001549022	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Trp628* variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs863225401) as “with likely pathogenic allele” and ClinVar (classified as pathogenic by True Health Diagnostics and likely pathogenic by Mayo Clinic). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.1883G>A variant leads to a premature stop codon at position 628, 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 addition, this variant was identified by our laboratory in a patient with an MSH6-deficient colon tumour. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.