Submissions for variant NM_000179.3(MSH6):c.394_395del (p.Gln132fs)

dbSNP: rs1668698146

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001183686	SCV001349481	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-02	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 2 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001221843	SCV001393910	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-09-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln132Valfs*3) 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: 923196). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001183686	SCV002624963	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-26	criteria provided, single submitter	clinical testing	The c.394_395delCA pathogenic mutation, located in coding exon 2 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 394 to 395, causing a translational frameshift with a predicted alternate stop codon (p.Q132Vfs*3). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV003449601	SCV004187358	pathogenic	Lynch syndrome 5	2023-08-10	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	RCV001355819	SCV001550813	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Gln132Valfs*3 variant was not identified in the literature nor was it identified in dbSNP, ClinVar, COGR, Cosmic, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or InSiGHT Hereditary Tumors databases. The variant was not identified in the following control databases: 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.394_395del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 132 and leads to a premature stop codon at position 134. 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 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.