Submissions for variant NM_000179.3(MSH6):c.1139_1143del (p.Asp380fs)

dbSNP: rs587779206

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074636	SCV000107836	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000704633	SCV000833589	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-27	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: 89175). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 22495361, 26517685). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp380Alafs*6) 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	RCV001009985	SCV001170120	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	The c.1139_1143delATGAG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of 5 nucleotides at nucleotide positions 1139 to 1143, causing a translational frameshift with a predicted alternate stop codon (p.D380Afs*6). This mutation has been detected in multiple Lynch syndrome patients with colon or endometrial cancer (Okkels H et al. Appl Immunohistochem Mol Morphol. 2012 Oct;20(5):470-7; Jori B et al. Oncotarget. 2015 Dec 1;6(38):41108-22). 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.
Myriad Genetics, Inc.	RCV003450923	SCV004187377	pathogenic	Lynch syndrome 5	2023-08-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003478993	SCV004223164	pathogenic	Hereditary nonpolyposis colon cancer	2023-11-27	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1139_1143delATGAG (p.Asp380AlafsX6) 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. The variant was absent in 250970 control chromosomes. c.1139_1143delATGAG has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Jori_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26517685). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356254	SCV001551369	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.Asp380AlafsX6 variant was identified in 1 of 1630 proband chromosomes (frequency: 0.0006) from Dutch individuals or families with HNPCC (Okkels 2012). The variant was also identified in the following databases: dbSNP (ID: rs587779206) “With Pathogenic allele”, ClinVar (pathogenic, reviewed by expert panel (2013)), Clinvitae (1x), Insight Colon Cancer Gene Variant Database (1x as class 5), Insight Hereditary Tumors Database (7x). It was not identified in the following databases: Cosmic, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016). The p.Asp380alafsX6 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 380 and leads to a premature stop 6 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 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.