Submissions for variant NM_000179.3(MSH6):c.2147_2148del (p.Thr716fs)

dbSNP: rs786204048

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000167893	SCV000218539	pathogenic	Lynch syndrome	2014-09-10	criteria provided, single submitter	clinical testing	This sequence change deletes two nucleotides from exon 4 of the MSH6 mRNA (c.2144_2145delAC), causing a frameshift at codon 716. This creates a premature translational stop signal 38 codons downstream (p.Thr716Serfs*39) and is expected to result in an absent or disrupted protein product. This sequence change has been reported in the literature and is not present in population databases. This sequence change was reported in an individual affected with colorectal cancer, who also was screened for and tested negative for mutations in other Lynch syndrome related genes. Screening of the tumor sample from this individual revealed microsatellite instability, but no loss of expression of any of the mismatch repair proteins (PMID: 21868491). This sequence change is also known as c.2147_2148delCA in the literature. In summary, this sequence change is absent from the general population and is expected to create an absent or aberrant MSH6 protein. For these reasons, this sequence change has been classified as Pathogenic.
Ambry Genetics	RCV000491742	SCV000580152	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-11	criteria provided, single submitter	clinical testing	The c.2147_2148delCA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 2147 to 2148, causing a translational frameshift with a predicted alternate stop codon (p.T716Sfs*39). This mutation has been reported in a family that met Amsterdam criteria where the proband was diagnosed with ascending colon cancer at the age of 79. While the tumor showed microsatellite instability, IHC staining showed MLH1, MSH2, MSH6, and PMS2 proteins were intact (Pérez-Carbonell L et al. Gut 2012 Jun;61:865-72). This variant was also reported in a female diagnosed with ampullary cancer, gastric cancer, and CML by age 40 (Cloyd JM et al. J Gastrointest Cancer, 2018 Mar;49:93-96). 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.
Invitae	RCV001380732	SCV001578884	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-05-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr716Serfs*39) 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 premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 21868491). ClinVar contains an entry for this variant (Variation ID: 428317). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003313083	SCV004012503	pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history including colorectal, pancreatic, and other cancers (Perez-Carbonell et al., 2012; Meric-Bernstam et al., 2016; Cloyd et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also reported as 2144_2145delAC; This variant is associated with the following publications: (PMID: 35449176, 29946497, 21868491, 29238914, 26787237)
Myriad Genetics, Inc.	RCV003449297	SCV004185675	pathogenic	Lynch syndrome 5	2023-08-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003313083	SCV004221170	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	The MSH6 c.2147_2148del (p.Thr716Serfs*39) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in individuals with colorectal cancer (PMID: 21868491 (2012)), biliary tract cancer and gastric cancer (PMID: 29238914 (2018)), and in a pancreatic tumor specimen (PMID: 26787237 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357870	SCV001553461	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.Thr716SerfsX39 variant was identified in 1 of 4186 proband chromosomes (frequency: 0.0002) from Spanish individuals or families with CRC, the affected case meeting Amsterdam criteria (Perez-Cabornell_2011_21868491). The variant was also identified in dbSNP (ID: rs786204048) “With Pathogenic allele”, ClinVar (classified pathogenic by Invitae and Ambry Genetics), Clinvitae (2x), UMD-LSDB (2x as causal), Insight Colon Cancer Gene Variant Database (1x), Insight Hereditary Tumors Database (1x), and was not identified in GeneInsight-COGR, Cosmic, MutDB, 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.2147_2148delCA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 716 and leads to a premature stop codon 39 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.