Submissions for variant NM_000179.3(MSH6):c.3766dup (p.Tyr1256fs)

dbSNP: rs1553333127

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482164	SCV000570958	pathogenic	not provided	2016-07-11	criteria provided, single submitter	clinical testing	This duplication of one nucleotides in MSH6 is denoted c.3766dupT at the cDNA level and p.Tyr1256LeufsX19 (Y1256LfsX19) at the protein level. The surrounding sequence is AGAT[T]ATTC. The duplication causes a frameshift which changes a Tyrosine to a Leucine at codon 1256, and creates a premature stop codon at position 19 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851215	SCV002237902	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1256Leufs*19) 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: 421675). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004791493	SCV005403826	pathogenic	Lynch syndrome 5	2024-07-10	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.