Submissions for variant NM_000179.2(MSH6):c.3142C>T (p.Gln1048Ter) (rs200492211)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000202056	SCV000149310	pathogenic	not provided	2018-06-20	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH6 c.3142C>T at the cDNA level and p.Gln1048Ter (Q1048X) at the protein level. The substitution creates a nonsense variant, changing a Glutamine to a premature stop codon (CAG>TAG). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with colorectal cancer and one with endometrial cancer whose tumors showed loss of MSH6 via mismatch repair immunohistochemistry (Talseth-Palmer 2010, Buchanan 2014). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV000490956	SCV000580150	pathogenic	Hereditary cancer-predisposing syndrome	2018-10-11	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000500240	SCV000592622	pathogenic	Lynch syndrome	2015-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV000544323	SCV000624821	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-11-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1048*) 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 reported in individuals affected with Lynch syndrome and colorectal and endometrial cancer (PMID: 20487569, 24323032, 27064304). ClinVar contains an entry for this variant (Variation ID: 127580). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic	RCV000202056	SCV000257233	pathogenic	not provided		no assertion criteria provided	research

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