ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3647delG (rs1064795629)

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Total submissions: 4
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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 2018-01-02 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America 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 2019-10-17 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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 422205). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.

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