rs863224830
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_000179.3(MSH6):βc.4081_4082delβ(p.Ter1361AspfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. L1360L) has been classified as Likely benign.
Frequency
Consequence
NM_000179.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.4081_4082del | p.Ter1361AspfsTer2 | frameshift_variant | 10/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.4081_4082del | p.Ter1361AspfsTer2 | frameshift_variant | 10/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 1AN: 151872Hom.: 0 Cov.: 31 FAILED QC
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251044Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135712
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1457708Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 725424
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1AN: 151872Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74170
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 20, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 25, 2020 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 22, 2015 | This sequence change deletes 2 nucleotide from exon 10 of the MSH6 mRNA (c.4079_4080delTA). This deletion disrupts the translational stop signal of the MSH6 mRNA and it is expected to extend the length of the MSH6 protein by 2 additional amino acid residues (p.*1361Aspext*2). The effect of this extension on protein function is uncertain. This variant has not been published in the literature and is not present in population databases. In summary, this is a novel stop-loss variant with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 16, 2021 | This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with MSH6-related conditions. This sequence change disrupts the translational stop signal of the MSH6 mRNA. It is expected to extend the length of the MSH6 protein by one additional amino acid residue. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 13, 2021 | The c.4081_4082delTA variant, located in coding exon 10 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 4081 to 4082, causing a translational frameshift with a predicted alternate stop codon (p.*1361Dext*1). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by one amino acid. The exact functional effect of the altered amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at