rs878853711
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):c.2056_2060delinsCTTCTACCTCAAAAA(p.Gly686LeufsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G686G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000179.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.2056_2060delinsCTTCTACCTCAAAAA | p.Gly686LeufsTer15 | frameshift_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.2056_2060delinsCTTCTACCTCAAAAA | p.Gly686LeufsTer15 | frameshift_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Lynch syndrome 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 16, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Hereditary nonpolyposis colon cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 16, 2021 | Variant summary: MSH6 c.2056_2060delins15 (p.Gly686LeufsX15) 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 (examples: c.2150_2153delTCAG p.Val717AlafsX18; c.2230dupG p.Glu744GlyfsX12). The variant was absent in 250560 control chromosomes. To our knowledge, no occurrence of c.2056_2060delins15 in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Lynch syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2017 | This sequence change deletes 5 nucleotides and inserts 15 nucleotides in exon 4 of the MSH6 mRNA (c.2056_2060delinsCTTCTACCTCAAAAA), causing a frameshift at codon 686. This creates a premature translational stop signal (p.Gly686Leufs*15) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 09, 2021 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Gly686Leufs*15) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at