Submissions for variant NM_000179.2(MSH6):c.2061T>A (p.Cys687Ter) (rs267608068)

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Total submissions: 7

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074710	SCV000107917	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000162397	SCV000212720	pathogenic	Hereditary cancer-predisposing syndrome	2016-03-09	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Other acmg-defined mutation (i.e. initiation codon or gross deletion);Other data supporting pathogenic classification
GeneDx	RCV000201965	SCV000490620	pathogenic	not provided	2017-10-26	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH6 c.2061T>A at the cDNA level and p.Cys687Ter (C687X) atthe protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon(TGT>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in an individual with a tubular adenoma and in a Scottish familywith multiple cases of colorectal or Lynch syndrome cancers (Pino 2009, Baglietto 2010), and is consideredpathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000074710	SCV000592595	pathogenic	Lynch syndrome	2015-08-11	criteria provided, single submitter	clinical testing
Invitae	RCV000530716	SCV000624721	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys687*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Lynch syndrome (PMID: 19324997). ClinVar contains an entry for this variant (Variation ID: 89246). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Color	RCV000162397	SCV000685252	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic	RCV000201965	SCV000257218	likely pathogenic	not provided		no assertion criteria provided	clinical testing

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