Submissions for variant NM_000179.3(MSH6):c.3804dup (p.Cys1269fs)

dbSNP: rs267608118

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074937	SCV000108151	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000214022	SCV000275659	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	clinical testing	The c.3804dupA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of A at nucleotide position 3804, causing a translational frameshift with a predicted alternate stop codon (p.C1269Mfs*6). This duplication has been reported in six Norwegian Lynch syndrome families and in a patient diagnosed with pancreatic cancer and endometrial cancer with a family history of colon and breast cancers (Sjursen W et al. J. Med. Genet. 2010 Sep; 47(9):579-85; Hu C et al. Cancer Epidemiol. Biomarkers Prev. 2016 Jan;25:207-11). This alteration has also been identified in an individual meeting Amsterdam criteria (Stormorken AT et al. J Clin Oncol, 2005 Jul;23:4705-12). 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.
GeneDx	RCV000214836	SCV000279615	pathogenic	not provided	2016-10-14	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MSH6 is denoted c.3804dupA at the cDNA level and p.Cys1269MetfsX6 (C1269MfsX6) at the protein level. The normal sequence, with the base that is duplicated in braces, is agGC[A]TGCA, where the capital letters are exonic and the lower case are intronic. The duplication causes a frameshift which changes a Cysteine to a Methionine at codon 1269, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3804dupA has been identified in individuals with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) (Stormorken 2005, Sjursen 2010). We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684821	SCV000551241	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys1269Metfs*6) 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 premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 20587412, 26483394). ClinVar contains an entry for this variant (Variation ID: 89469). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000214022	SCV000905459	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant is located in the MSH6 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. 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.
Myriad Genetics, Inc.	RCV003450981	SCV004188303	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.
Baylor Genetics	RCV003466951	SCV004198174	pathogenic	Endometrial carcinoma	2024-02-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000214836	SCV005623494	pathogenic	not provided	2024-08-21	criteria provided, single submitter	clinical testing	The MSH6 c.3804dup (p.Cys1269Metfs*6) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in individuals and/or families with colorectal cancer (PMID: 16034045 (2005), 20587412 (2010)), pancreatic cancer (PMID: 29922827 (2018)) and prostate cancer (PMID: 36623239 (2023)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). ClinVar contains an entry for this variant (URL: www.ncbi.nlm.nih.gov/clinvar, Variation ID: 89469). Based on the available information, this variant is classified as pathogenic. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.