Submissions for variant NM_000179.3(MSH6):c.3312del (p.Phe1104fs)

dbSNP: rs267608092

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074838	SCV000108050	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000574023	SCV000670100	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-17	criteria provided, single submitter	clinical testing	The c.3312delT pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 3312, causing a translational frameshift with a predicted alternate stop codon (p.F1104Lfs*11). This mutation has been identified in multiple HNPCC/Lynch syndrome patients whose tumors demonstrated absence of the MSH6 protein by IHC (Malander S et al. Gynecol. Oncol. 2006 May;101:238-43; Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5; Lagerstedt-Robinson K et al. Oncol Rep. 2016 Nov;36(5):2823-2835). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Color Diagnostics, LLC DBA Color Health	RCV000574023	SCV000690343	pathogenic	Hereditary cancer-predisposing syndrome	2017-08-30	criteria provided, single submitter	clinical testing
Invitae	RCV000630183	SCV000751139	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe1104Leufs*11) 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 variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 89371). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003450963	SCV004185867	pathogenic	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.