rs373718658
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000038.6(APC):c.14C>A(p.Ser5Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S5S) has been classified as Likely benign.
Frequency
Consequence
NM_000038.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.14C>A | p.Ser5Ter | stop_gained | 2/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.14C>A | p.Ser5Ter | stop_gained | 2/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461454Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727044
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 411429). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser5*) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 24, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2021 | The p.S5* variant (also known as c.14C>A), located in coding exon 1 of the APC gene, results from a C to A substitution at nucleotide position 14. This changes the amino acid from a serine to a stop codon within coding exon 1. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay; however, this alteration and others loss-of-function alterations that occur at the extreme N-terminus of APC have been observed in numerous individuals who do not have a personal or family history that is consistent with or suggestive of APC associated disease (Ambry internal data). This suggests the use of an alternate translation initiation site which could be imparted by the second, in-frame methionine located at p.M18. Evidence for the use of this methionine or the functional characteristics of an APC protein lacking amino acids 1-17 have not been published. 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