Submissions for variant NM_000179.3(MSH6):c.3268_3274del (p.Glu1090fs)

dbSNP: rs587779259

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074833	SCV000108044	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000483834	SCV000567781	pathogenic	not provided	2015-08-28	criteria provided, single submitter	clinical testing	This deletion of 7 nucleotides in MSH6 is denoted c.3268_3274delGAGCTTA at the cDNA level and p.Glu1090LysfsX23 (E1090KfsX23) at the protein level. The normal sequence, with the bases that are deleted in braces, is CTTA[GAGCTTA]AAGG. The deletion causes a frameshift, which changes a Glutamic Acid to a Lysine at codon 1090, and creates a premature stop codon at position 23 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3268_3274delGAGCTTA, also reported as c.3264_3270del, has been observed in at least one individual with Lynch syndrome (Canard 2012). we consider this variant to be pathogenic.
Ambry Genetics	RCV000573738	SCV000670037	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	The c.3268_3274delGAGCTTA pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of 7 nucleotides at nucleotide positions 3268 to 3274, causing a translational frameshift with a predicted alternate stop codon (p.E1090Kfs*23). This mutation has been previously reported in a an Australian cohort of individuals/families suspected of having HNPCC/Lynch syndrome based on clinical and/or family history (Talseth-Palmer BA et al. Hered Cancer Clin Pract. 2010 May;8:5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000629992	SCV000750948	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1090Lysfs*23) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89366). This variant is also known as c.3264_3270del. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 20487569, 21879275, 27601186). This variant is not present in population databases (gnomAD no frequency).
Myriad Genetics, Inc.	RCV003450962	SCV004188249	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.
Revvity Omics, Revvity	RCV000483834	SCV004238289	likely pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358489	SCV001554237	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Glu1090LysfsX23 variant was identified in 1 of 156 proband chromosomes (frequency: 0.006) from individuals or families with colorectal cancer (Talseth-Palmer 2010). The variant was also identified in dbSNP (ID: rs587779259) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic by InSight) and UMD (12x with a “causal” classification). The variant was not found in the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the Exome Aggregation Consortium, the genome Aggregation Database (beta), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database. However, this information is not predictive enough to assume pathogenicity. The c.3268_3274del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1090 and leads to a premature stop codon 23 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.