Submissions for variant NM_000179.3(MSH6):c.3477C>G (p.Tyr1159Ter)

dbSNP: rs398123231

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000228304	SCV000283808	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1159*) 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 present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 21642682). ClinVar contains an entry for this variant (Variation ID: 237193). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000580568	SCV000685409	pathogenic	Hereditary cancer-predisposing syndrome	2016-12-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000657748	SCV000779500	pathogenic	not provided	2018-01-17	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3477C>G at the cDNA level and p.Tyr1159Ter (Y1159X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781603	SCV000919775	pathogenic	Lynch syndrome	2018-11-21	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3477C>G (p.Tyr1159X) 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. p.Asp1171fsX5, p.Arg1172fsX5, p.His1203fsX12). The variant allele was found at a frequency of 4.1e-06 in 246160 control chromosomes. c.3477C>G has not been reported in the literature in individuals affected with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different mutation resulting in the same amino acid change has been classified as pathogenic by our lab (c.3476dupA, p.Tyr1159X). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000580568	SCV001181868	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	The p.Y1159* pathogenic mutation (also known as c.3477C>G), located in coding exon 6 of the MSH6 gene, results from a C to G substitution at nucleotide position 3477. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. A different substitution (c.3477C>A) resulting in the same premature stop codon has been reported in a family with Lynch syndrome (Bonadona V et al. JAMA 2011 Jun;305:2304-10). In addition to the clinical data presented in the literature, 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.
CeGaT Center for Human Genetics Tuebingen	RCV000657748	SCV002585791	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PM2
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003137833	SCV003806427	pathogenic	Papillary carcinoma of the corpus uteri	2023-03-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003454692	SCV004185851	pathogenic	Lynch syndrome 5	2023-08-23	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.