Submissions for variant NM_000179.3(MSH6):c.3037_3041del (p.Lys1013fs)

dbSNP: rs587782712

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132188	SCV000187268	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	clinical testing	The c.3037_3041delAAGAA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of five nucleotides at positions 3037 to 3041, causing a translational frameshift with a predicted alternate stop codon (p.K1013Vfs*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.
Invitae	RCV000200490	SCV000255261	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1013Valfs*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 premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 27064304). ClinVar contains an entry for this variant (Variation ID: 142781). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000202303	SCV000565221	pathogenic	not provided	2023-04-24	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28514183, 28152038, 26023681, 27064304, 28528517, 32719484, 30787465)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202303	SCV000601555	pathogenic	not provided	2022-12-13	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in at least one individual with Lynch Syndrome (PMID: 27064304 (2016)) and in individuals with personal and/or family history of colon cancer (PMIDs: 26023681(2015) and 28528517 (2017)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155083	SCV000919756	pathogenic	Hereditary nonpolyposis colon cancer	2023-02-09	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3037_3041delAAGAA (p.Lys1013ValfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 218886 control chromosomes. c.3037_3041delAAGAA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Sjursen_2016, Morak_2017) and Lynch Syndrome (Yamashita_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000132188	SCV001359871	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides from 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 Lynch syndrome (PMID: 27064304), as well as in individuals having personal or family history of colorectal cancer (PMID: 26023681, 28528517). 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.
Myriad Genetics, Inc.	RCV003453095	SCV004188239	pathogenic	Lynch syndrome 5	2023-08-22	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	RCV003462036	SCV004195706	pathogenic	Endometrial carcinoma	2023-06-26	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003453095	SCV004228240	pathogenic	Lynch syndrome 5	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change results from a deletion of five nucleotides at positions 3037 to 3041, causing a translational frameshift with a predicted alternate stop codon (p.K1013Vfs*3). 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) as well as in individuals having personal or family history of colon cancer (PMID: 26023681, 28528517). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 27064304). ClinVar contains an entry for this variant (Variation ID: 142781). For these reasons, this variant has been classified as Pathogenic. This mutation previously detected in comprehensive cancer panel done for the same patient . Heterozygous pathogenic mutations in the MSH6 gene are associated with Lynch syndrome 5 ( MIM:# 614350)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202303	SCV004565221	pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing	The MSH6 c.3037_3041del; p.Lys1013ValfsTer3 variant (rs587782712) is reported in the literature in individuals with Lynch syndrome (Morak 2017, Sjursen 2016, Yamashita 2021). This variant is also reported in ClinVar (Variation ID: 142781). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting five nucleotides, 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: Morak M et al. Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6. Fam Cancer. 2017 Oct;16(4):491-500. PMID: 28528517. Sjursen W et al. Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations. Mol Genet Genomic Med. 2016 Jan 11;4(2):223-31. PMID: 27064304. Yamashita K et al. Interval between the First Cancer and the Genetic Diagnosis in Lynch Syndrome Probands. Intern Med. 2021 Sep 1;60(17):2719-2724. PMID: 33746161.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017417	SCV004847555	pathogenic	Lynch syndrome	2022-08-26	criteria provided, single submitter	clinical testing	The p.Lys1013ValfsX3 in MSH6 has been reported in one in individual with Lynch syndrome, 1 individual with colon cancer, and 1 individual with a family history of colon cancer (Foley 2015 PMID: 26023681, Sjursen 2016 PMID: 27064304, Morak 2017 PMID: 28528517), and has been identified 0.001% (1/68038) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). his variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1013 and leads to a premature termination codon 3 amino acids downstream. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary the variante meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202303	SCV000257232	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355368	SCV001550240	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Lys1013ValfsX3 variant was identified in 2 of 1192 proband chromosomes (frequency: 0.002) from individuals or families with Lynch Syndrome and colon cancer (Foley 2015, Sjursen 2016). The variant was also identified in the following databases: dbSNP (ID: rs587782712) as "With Pathogenic allele", ClinVar (4x pathogenic, 1x likely pathogenic), Clinvitae (2x pathogenic), and Insight Hereditary Tumors Database. The variant was not identified in Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, or Mismatch Repair Genes Variant Database. The variant was also identified by our laboratory in one individual with Lynch Syndrome. The variant was not found 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.3037_3041delAAGAA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1013 and leads to a premature stop codon at position 1015. 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.