rs876660375
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PS4_ModeratePM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.8514C>A variant in APC is a variant predicted to cause a premature stop codon at position 2838 (p.Tyr2838*) in exon 16, downstream of codon 2645. As a result, the PVS1 rule is not applicable. This variant has been reported in 2 probands meeting phenotype criteria, resulting in a total phenotype score of 2 (PS4_moderate, Ambry and Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this is a Variant of Unknown Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_moderate and PM2_supporting. (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16039798/MONDO:0021056/089
Frequency
Consequence
NM_000038.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.8514C>A | p.Tyr2838Ter | stop_gained | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.8514C>A | p.Tyr2838Ter | stop_gained | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2
Uncertain significance, reviewed by expert panel | curation | ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel | Feb 26, 2023 | The c.8514C>A variant in APC is a variant predicted to cause a premature stop codon at position 2838 (p.Tyr2838*) in exon 16, downstream of codon 2645. As a result, the PVS1 rule is not applicable. This variant has been reported in 2 probands meeting phenotype criteria, resulting in a total phenotype score of 2 (PS4_moderate, Ambry and Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this is a Variant of Unknown Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_moderate and PM2_supporting. (VCEP specifications version 1; date of approval: 12/12/2022). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2020 | 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 APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 486740). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr2838*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the APC protein. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2021 | The p.Y2838* variant (also known as c.8514C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 8514. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. This substitution and subsequent stop codon occur at the 3' terminus of APC and impact only the last 6 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time; however, structural analysis suggests this deletion removes a known motif (Thr2841-Ser2842-Val2843) needed for protein binding involved in regulation of protein function (Slep KC et al, PLoS ONE 2012; 7(11):e50097 ; Zhang Z et al, PLoS ONE 2011 ; 6(8):e23507). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at