Submissions for variant NM_000179.3(MSH6):c.3733_3739dup (p.Thr1247fs)

dbSNP: rs1670054668

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193099	SCV001361707	likely pathogenic	Hereditary nonpolyposis colon cancer	2019-04-01	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3733_3739dupTTTTCAA (p.Thr1247IlefsX30) 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 (eg. c.3799_3800delAT (p.Met1267fsX7), c.3814_3827dupGAAAATGAATGTGA(p.Asp1277fsX55)). The variant was absent in 245976 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3733_3739dupTTTTCAA in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003449625	SCV004187278	pathogenic	Lynch syndrome 5	2023-08-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478727	SCV004222008	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. The variant has not been reported in individuals with MSH6-related diseases in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Invitae	RCV003759028	SCV004423224	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1247Ilefs*30) 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 variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 928745). For these reasons, this variant has been classified as Pathogenic.