Submissions for variant NM_000179.3(MSH6):c.3932_3935dup (p.Ile1313fs)

dbSNP: rs267608127

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074951	SCV000108166	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000479887	SCV000568733	pathogenic	not provided	2016-03-28	criteria provided, single submitter	clinical testing	This duplication of 4 nucleotides in MSH6 is denoted c.3932_3935dupAAGT at the cDNA level and p.Ile1313SerfsX7 (I1313SfsX7) at the protein level. The normal sequence, with the bases that are duplicated in braces, is GAGG[AAGT]TATT. The duplication causes a frameshift which changes an Isoleucine to a Serine at codon 1313, and creates a premature stop codon at position 7 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 48 amino acids are no longer translated correctly, and it is predicted to cause loss of normal protein function through protein truncation. This variant disrupts an MSH2 binding site in domain V of the MutS domain (Kariola 2002, Terui 2013). MSH6 c.3932_3935dupAAGT, also known as c.3932_3935dup4 using alternative nomenclature, has been observed in at least two individuals from a single family, one of whom had a diagnosis of colorectal or endometrial cancer (Ramsoekh 2008). The adjacent variant MSH6 c.3934_3937dupGTTA, which also results in a frameshift at this residue (p.Ile1313SerfsX7), has been observed in at least two other individuals with a clinical history of a Lynch syndrome associated cancer and/or colon polyps, one of whom was also diagnosed with breast cancer (Susswein 2015, Yurgelun 2015). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae	RCV001854285	SCV002150083	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-05	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 89483). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 15236168, 19851887, 21155762, 24440087). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18625694). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile1313Serfs*7) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the MSH6 protein.
Ambry Genetics	RCV002371906	SCV002626106	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-12	criteria provided, single submitter	clinical testing	The c.3932_3935dupAAGT pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of AAGT at nucleotide position 3932, causing a translational frameshift with a predicted alternate stop codon (p.I1313Sfs*7). This mutation was reported in a family meeting either Amsterdam II or revised Bethesda criteria (Ramsoekh D et al. Gut 2008 Nov;57:1539-44). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003450983	SCV004185898	pathogenic	Lynch syndrome 5	2023-08-28	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 Pathology and Laboratory Medicine, Sinai Health System	RCV000479887	SCV001553017	uncertain significance	not provided		no assertion criteria provided	clinical testing