Submissions for variant NM_000179.3(MSH6):c.3463C>T (p.Gln1155Ter)

dbSNP: rs1553332166

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568670	SCV000670065	pathogenic	Hereditary cancer-predisposing syndrome	2017-03-30	criteria provided, single submitter	clinical testing	The p.Q1155* pathogenic mutation (also known as c.3463C>T), located in coding exon 6 of the MSH6 gene, results from a C to T substitution at nucleotide position 3463. This changes the amino acid from a glutamine to a stop codon within coding exon 6. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780477	SCV000917761	likely pathogenic	Lynch syndrome	2018-05-14	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3463C>T (p.Gln1155X) 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 (e.g. c.3476dupA (p.Tyr1159X), c.3513_3514delTA (p.Asp1171fsX5), c.3514dupA (p.Arg1172fsX5)). The variant was absent in 246166 control chromosomes. c.3463C>T has been reported in the literature in an individual with bladder cancer (Mandelker 2017). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000568670	SCV001339882	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 6 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with bladder cancer (PMID: 28873162, 30376427). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV001853718	SCV002235143	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-10	criteria provided, single submitter	clinical testing	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: 483851). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln1155*) 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).
Myriad Genetics, Inc.	RCV003451256	SCV004185608	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.