Submissions for variant NM_000179.2(MSH6):c.3647delG

dbSNP: rs1064795629

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481123	SCV000571613	pathogenic	not provided	2016-09-02	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in MSH6 is denoted c.3647delG at the cDNA level and p.Gly1216GlufsX12 (G1216EfsX12) at the protein level. The normal sequence, with the base that is deleted in braces, is ACAG[G]AAGA. The deletion causes a frameshift which changes a Glycine to a Glutamic Acid at codon 1216, and creates a premature stop codon at position 12 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Ambry Genetics	RCV000491618	SCV000580169	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	The c.3647delG pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 3647, causing a translational frameshift with a predicted alternate stop codon (p.G1216Efs*12). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194363	SCV001363851	likely pathogenic	Hereditary nonpolyposis colon cancer	2019-05-09	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3647delG (p.Gly1216GlufsX12) 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 also affects an exonic splice region, i.e. the first nucleotide of exon 8, and therefore it could affect mRNA splicing, leading to a significantly altered protein sequence. Some computational tools predict significant impact on normal splicing: one predicts the variant abolishes a 3' acceptor site, while another one predicts the variant weakens a 3' acceptor site. These predictions however have not been confirmed by functional studies. The variant was absent in 251160 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3647delG in individuals affected with Hereditary Non-Polyposis Colon Cancer 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, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001211419	SCV001382960	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly1216Glufs*12) 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 422205). 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).
Myriad Genetics, Inc.	RCV003449221	SCV004185714	pathogenic	Lynch syndrome 5	2023-08-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.