Submissions for variant NM_000179.3(MSH6):c.2348_2349del (p.Leu782_Cys783insTer)

dbSNP: rs267608065

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074739	SCV000107948	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000491787	SCV000580301	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-05	criteria provided, single submitter	clinical testing	The c.2348_2349delGT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 2348 to 2349, causing a translational frameshift with a predicted alternate stop codon (p.C783*). The alteration was initially reported in an individual meeting revised Bethesda criteria who was diagnosed with colon cancer at the age of 47 and had secondary neoplasia diagnosed at 47 as well as 48. Tumor analysis showed MSI-H and loss of MSH6 by IHC (Steinke V et al. Eur. J. Hum. Genet. 2008 May; 16(5):587-92). This alteration was also identified in an individual diagnosed with colon cancer at the age of 38, but had no family history of cancer. Although he did not fulfill Amsterdam II criteria, IHC tumor analysis showed isolated loss of MSH6 (Talseth-Palmer B.A. et al. Hered Cancer Clin Pract 2010;8(1):5). 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	RCV000556290	SCV000624749	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys783*) 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 colon cancer (PMID: 18301448, 20487569). ClinVar contains an entry for this variant (Variation ID: 89274). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657810	SCV000779565	pathogenic	not provided	2017-01-23	criteria provided, single submitter	clinical testing	This deletion of two nucleotides is denoted MSH6 c.2348_2349delGT at the cDNA level and p.Cys783Ter (C783X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CTCT[delGT]AACC. The deletion creates a nonsense variant, which changes a Cysteine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.2348_2349delGT has been reported in two individuals with colorectal cancer whose tumors showed loss of MSH6 protein on immunohistochemistry (Steinke 2008, Talseth-Palmer 2010). This variant is considered pathogenic.
Myriad Genetics, Inc.	RCV003450945	SCV004187131	pathogenic	Lynch syndrome 5	2023-08-17	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.
Baylor Genetics	RCV001353421	SCV004196365	pathogenic	Endometrial carcinoma	2021-07-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353421	SCV000592607	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.Cys783X variant was identified in individuals with HNPCC although no frequency data was provided (Steinke 2008, Talseth-Palmer 2010). The variant was also identified in dbSNP (ID: rs267608065) “With pathogenic allele”, the Clinvitae database as pathogenic, InSiGHT Colon Cancer Gene Variant Database as pathogenic, the ClinVar database (classified as a pathogenic variant and reviewed by an expert panel). The p.Cys783X variant leads to a premature stop codon at position 783, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
CZECANCA consortium	RCV001353421	SCV003804328	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing