Submissions for variant NM_000179.3(MSH6):c.3729_3732dup (p.Phe1245fs)

dbSNP: rs587779288

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074922	SCV000108135	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV001381216	SCV001579519	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-06-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89454). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 20028993, 26517685). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe1245Ilefs*31) 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).
Ambry Genetics	RCV002345377	SCV002619576	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-02	criteria provided, single submitter	clinical testing	The c.3729_3732dupATTA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of ATTA at nucleotide position 3729, causing a translational frameshift with a predicted alternate stop codon (p.F1245Ifs*31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration has been identified in multiple unrelated Dutch families with Lynch syndrome (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Jóri B et al. Oncotarget 2015 Dec;6:41108-22). 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.
Revvity Omics, Revvity	RCV003137608	SCV003822260	pathogenic	not provided	2021-12-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450978	SCV004187345	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.