Submissions for variant NM_000179.3(MSH6):c.1572C>G (p.Tyr524Ter)

dbSNP: rs587779215

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074665	SCV000107867	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000491949	SCV000580121	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-21	criteria provided, single submitter	clinical testing	The p.Y524* pathogenic mutation (also known as c.1572C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1572. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. This variant has been identified in a Spanish patient with primary endometrial cancer (Rubio I et al. Oncology. 2016;91(3):171-6). 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.
Invitae	RCV000798747	SCV000938377	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr524*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant has been observed in an individual affected with endometrial cancer (PMID: 27398995). ClinVar contains an entry for this variant (Variation ID: 89202). This variant is not present in population databases (ExAC no frequency).
GeneDx	RCV002266921	SCV002549209	pathogenic	not provided	2022-07-14	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals referred for hereditary colorectal cancer testing (Rey et al., 2017); This variant is associated with the following publications: (PMID: 28152038, 28502729)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469003	SCV002765949	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-11-25	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1572C>G (p.Tyr524X) 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. The variant was absent in 251322 control chromosomes (gnomAD). c.1572C>G has been reported in the literature in individuals with a clinical suspicion for HNPCC (example: Rubio_2016 and Feliubadal_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003450926	SCV004188233	pathogenic	Lynch syndrome 5	2023-08-14	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.
Color Diagnostics, LLC DBA Color Health	RCV000491949	SCV004357600	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 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 endometrial cancer (PMID: 27398995). 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.