Submissions for variant NM_000179.3(MSH6):c.1189dup (p.Tyr397fs)

dbSNP: rs1553412609

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480464	SCV000566349	pathogenic	not provided	2015-04-22	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MSH6 is denoted c.1189dupT at the cDNA level and p.Tyr397LeufsX4 (Y397LfsX4) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACTC[T]ATGT. The duplication causes a frameshift, which changes a Tyrosine to a Leucine at codon 397, and creates a premature stop codon at position 4 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.
Invitae	RCV001388502	SCV001589505	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr397Leufs*4) 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: 418928). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002341130	SCV002641705	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-25	criteria provided, single submitter	clinical testing	The c.1189dupT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 1189, causing a translational frameshift with a predicted alternate stop codon (p.Y397Lfs*4). This mutation was identified in a cohort of women undergoing multigene panel testing for hereditary cancer risk; this individual had a personal history of colorectal and endometrial cancer (Roberts ME et al. Genet Med, 2018 10;20:1167-1174). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000480464	SCV004011162	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PM2
Myriad Genetics, Inc.	RCV003449175	SCV004185740	pathogenic	Lynch syndrome 5	2023-08-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017637	SCV004847756	likely pathogenic	Lynch syndrome	2019-05-08	criteria provided, single submitter	clinical testing	The p.Tyr397LeufsX4 variant in MSH6 has not been previously reported in individuals with Lynch syndrome and was absent from large population studies. It has been reported in ClinVar (variation ID 418928). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 379 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, thep.Tyr397LeufsX4 variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1; PM2.