Submissions for variant NM_000179.3(MSH6):c.3609_3612del (p.His1203fs)

dbSNP: rs587779274

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074893	SCV000108105	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267831	SCV002552351	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514332	SCV003524642	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-09-01	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with MSH6-related conditions (PMID: 16283678, 22495361). For these reasons, this variant has been classified as Pathogenic. This variant is also known as c.3607_3610delCATG or c.3603_3606delAGTG. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His1203Glnfs*12) 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).
Myriad Genetics, Inc.	RCV003450975	SCV004188279	pathogenic	Lynch syndrome 5	2023-08-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000074893	SCV005689680	pathogenic	Lynch syndrome	2025-02-04	criteria provided, single submitter	clinical testing	PVS1; PM2_SUP; PM3
OMIM	RCV004576919	SCV000029713	pathogenic	Mismatch repair cancer syndrome 1	2005-12-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004537279	SCV004711276	pathogenic	MSH6-related disorder	2024-01-18	no assertion criteria provided	clinical testing	The MSH6 c.3609_3612delTGCA variant is predicted to result in a frameshift and premature protein termination (p.His1203Glnfs*12). This variant along with a second variant in this gene was reported in at least one individual with hereditary nonpolyposis colorectal cancer (reported as c.3607_3610delCATG, Okkels et al 2012. PubMed ID: 22495361). This variant in the compound heterozygous condition along with a second variant in this gene was reported in two siblings with Neurofibromatosis, type 1 (Ostergaard et al 2005. PubMed ID: 16283678). In the homozygous condition, this variant was reported in several individuals with clinical features overlapping with constitutional mismatch repair deficiency and Tuberous Sclerosis complex (reported as c.3603_3606del, Rootman et al. 2020. PubMed ID: 31730237). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant was reported as pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/89425/). This variant is interpreted as pathogenic.