Submissions for variant NM_000179.3(MSH6):c.741del (p.Lys247fs)

dbSNP: rs267608041

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231668	SCV000283855	pathogenic	Lynch syndrome	2015-12-07	criteria provided, single submitter	clinical testing	This sequence change deletes 1 nucleotide from exon 4 of the MSH6 mRNA (c.741delA), causing a frameshift at codon 247. This creates a premature translational stop signal (p.Lys247Asnfs*32) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in a germline sample in the literature, truncating variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic.
Invitae	RCV001057806	SCV001222321	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 237213). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 26099011). This variant is present in population databases (rs267608041, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Lys247Asnfs*32) 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).
Ambry Genetics	RCV002378963	SCV002668385	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-23	criteria provided, single submitter	clinical testing	The c.741delA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 741, causing a translational frameshift with a predicted alternate stop codon (p.K247Nfs*32). 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.	RCV003454696	SCV004188326	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.
Baylor Genetics	RCV003463643	SCV004195646	pathogenic	Endometrial carcinoma	2023-07-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002378963	SCV004357554	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 4 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. This variant has been reported in an individual affected with endometrioid carcinoma that exhibited microsatellite instability and loss of MLH1, PMS2, and MSH6 proteins by immunohistochemistry analyses (PMID: 26099011). This variant has been identified in 1/31128 chromosomes 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736652	SCV004564389	pathogenic	not provided	2023-02-28	criteria provided, single submitter	clinical testing	The MSH6 c.741del; p.Lys247AsnfsTer32 variant (rs267608041) is reported in the literature in two individuals affected with Lynch syndrome (Graham 2015, Pearlman 2019). This variant is also reported in ClinVar (Variation ID: 237213). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Graham RP et al. Heterogenous MSH6 loss is a result of microsatellite instability within MSH6 and occurs in sporadic and hereditary colorectal and endometrial carcinomas. Am J Surg Pathol. 2015 Oct;39(10):1370-6. PMID: 26099011. Pearlman R et al. Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome. J Med Genet. 2019 Jul;56(7):462-470. PMID: 30877237.
All of Us Research Program, National Institutes of Health	RCV000231668	SCV004836919	pathogenic	Lynch syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 4 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. This variant has been reported in an individual affected with endometrioid carcinoma that exhibited microsatellite instability and loss of MLH1, PMS2, and MSH6 proteins by immunohistochemistry analyses (PMID: 26099011). This variant has been identified in 1/31128 chromosomes 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358625	SCV001554416	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Lys247AsnfsX32 variant was identified in sporadic gastric and lynch syndrome suspected tumours as a somatic event (and not germline) in 4 of 176 proband chromosomes (frequency: 0.02) from Portuguese and Spanish individuals or families (Pinto 2008, Vargas-Parra 2017). The variant was also identified in dbSNP (ID: rs267608041) “With Pathogenic allele”, ClinVar (classified pathogenic by Invitae), Cosmic (3x in stomach carcinoma), Insight Colon Cancer Gene Variant Database (1x), Mismatch Repair Genes Variant Database (2x). The variant was not identified in Genesight-COGR, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Insight Hereditary Tumors Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.741delA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 247 and leads to a premature stop codon 32 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 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.