Submissions for variant NM_000179.3(MSH6):c.845dup (p.Asp284fs)

dbSNP: rs1553412283

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075039	SCV000108260	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000629720	SCV000750676	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp284Glyfs*2) 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 colorectal cancer (PMID: 18301448). ClinVar contains an entry for this variant (Variation ID: 89570). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003162480	SCV003855668	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	The c.845dupT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 845, causing a translational frameshift with a predicted alternate stop codon (p.D284G*2). This variant has been reported in individuals with Lynch syndrome/HNPCC (Steinke V et al. Eur J Hum Genet, 2008 May;16:587-92; Nowak JA et al. J Mol Diagn, 2017 01;19:84-91). 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.
Myriad Genetics, Inc.	RCV003450995	SCV004185667	pathogenic	Lynch syndrome 5	2023-08-10	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	RCV003460704	SCV004196342	pathogenic	Endometrial carcinoma	2021-12-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075039	SCV004848647	pathogenic	Lynch syndrome	2022-05-11	criteria provided, single submitter	clinical testing	The p.Asp284GlyfsX2 variant in MSH6 has been identified in 2 individuals with MSH6-associated cancer (Steinke 2008 PMID: 18301448, LMM pers. comm.). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89570). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 284 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting.