rs1057517544
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000038.6(APC):c.5952_5955delTGAA(p.Glu1985LeufsTer58) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000038.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.5952_5955delTGAA | p.Glu1985LeufsTer58 | frameshift_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+12574_228+12577delTGAA | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:2
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This sequence change creates a premature translational stop signal (p.Glu1985Leufs*58) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 859 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of APC-related conditions (PMID: 20223039). ClinVar contains an entry for this variant (Variation ID: 371809). This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.5952_5955delTGAA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides between positions 5952 and 5955, causing a translational frameshift with a predicted alternate stop codon (p.E1985Lfs*58). This alteration occurs at the 3' terminus of APC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 30% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in one German polyposis patient (Friedl W and Aretz S Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at