Submissions for variant NM_000179.3(MSH6):c.3938_3941dup (p.Gln1314fs)

dbSNP: rs267608126

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074953	SCV000108168	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000524196	SCV000551181	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1314Hisfs*6) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the MSH6 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with endometrial cancer (PMID: 18269114). ClinVar contains an entry for this variant (Variation ID: 89485). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Ala1320Glufs*6, p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491665	SCV000580378	pathogenic	Hereditary cancer-predisposing syndrome	2016-09-09	criteria provided, single submitter	clinical testing	The c.3938_3941dupTTCA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of TTCA at nucleotide position 3938, causing a translational frameshift with a predicted alternate stop codon. This mutation was reported in a patient with a history of endometrial cancer and a family history that met Amsterdam II criteria (Devlin LA et al. Ulster Med J, 2008 Jan;77:25-30). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074953	SCV000695898	pathogenic	Lynch syndrome	2016-04-27	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest results in a frameshift mutation causes a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest has not been observed in controls (ExAC, 1000 Gs or ESP) and has been reported in an individual diagnosed with endometrial cancer via a publication. A reputable database cites the variant with a classification of "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759145	SCV000888281	pathogenic	not provided	2018-08-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450984	SCV004188289	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	RCV001358303	SCV001553998	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.Gln1314HisfsX6 variant was identified in 1 of 536 proband chromosomes (frequency: 0.002) from a cohort of Irish individuals or families with HNPCC or sporadic endometrial cancer. The individual with the variant was an endometrial case meeting Amsterdam II criteria (Devlin_2008_18269114). The variant was also identified in dbSNP (ID: rs267608126) “With Pathogenic allele”, ClinVar (classified pathogenic, reviewed by an expert panel (2013); submitters: InSIGHT, Invitae and Ambry Genetics), Clinvitae (2x), Insight Colon Cancer Gene Variant Database, and Insight Hereditary Tumors Database (1x, class 5). The variant was not identified in Genesight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3938_3941dupTTAC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1314 and leads to a premature stop codon 6 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.