Submissions for variant NM_000179.3(MSH6):c.3163dup (p.Ala1055fs)

dbSNP: rs878853729

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233953	SCV000283784	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-11	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala1055Glyfs*11) 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). ClinVar contains an entry for this variant (Variation ID: 237178). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657255	SCV000778985	pathogenic	not provided	2022-05-13	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database.; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255467	SCV001431875	likely pathogenic	Hereditary nonpolyposis colon cancer	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3163dupG (p.Ala1055GlyfsX11) 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 245836 control chromosomes. To our knowledge, no occurrence of c.3163dupG in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV000657255	SCV002017568	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257529	SCV002535799	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-08-28	criteria provided, single submitter	curation
Ambry Genetics	RCV002257529	SCV002608469	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	The c.3163dupG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of G at nucleotide position 3163, causing a translational frameshift with a predicted alternate stop codon (p.A1055Gfs*11). 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.	RCV003454691	SCV004187316	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355483	SCV001550383	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Ala1055GlyfsX11 variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors 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 variant was identified in dbSNP (ID: rs878853729) as “With Pathogenic allele”, in ClinVar (classified pathogenic by Invitae), and Clinvitae (1x). The c.3163dupG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1055 and leads to a premature stop codon 11 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 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.