rs876661127
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate
The NM_000179.3(MSH6):c.4016_4017dup(p.Ser1340LeufsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,602,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1339A) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.4016_4017dup | p.Ser1340LeufsTer7 | frameshift_variant | 10/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.4016_4017dup | p.Ser1340LeufsTer7 | frameshift_variant | 10/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000134 AC: 2AN: 148958Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 247898Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133966
GnomAD4 exome AF: 0.0000200 AC: 29AN: 1453542Hom.: 0 Cov.: 32 AF XY: 0.0000207 AC XY: 15AN XY: 722896
GnomAD4 genome ? AF: 0.0000134 AC: 2AN: 148958Hom.: 0 Cov.: 31 AF XY: 0.0000276 AC XY: 2AN XY: 72460
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 04, 2021 | This variant inserts 2 nucleotides in exon 10 of the MSH6 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is not expected to trigger nonsense-mediated decay. This variant changes the C-terminal 21 codons in the reference MSH6 protein. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/277834 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2023 | The c.4016_4017dupCT variant, located in coding exon 10 of the MSH6 gene, results from a duplication of CT at nucleotide position 4016, causing a translational frameshift with a predicted alternate stop codon (p.S1340Lfs*7). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 21 amino acids of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2023 | Frameshift variant predicted to result in protein truncation as the last 21 amino acids are replaced with 6 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12019211, 17531815, 21120944, 30787465) - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2023 | 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. ClinVar contains an entry for this variant (Variation ID: 234626). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Ser1340Leufs*7) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the MSH6 protein. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 05, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at