rs879254149
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000038.6(APC):c.646-8T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,602,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000038.6 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.646-8T>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000257430.9 | NP_000029.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.646-8T>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_000038.6 | ENSP00000257430 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000262 AC: 38AN: 1450036Hom.: 0 Cov.: 28 AF XY: 0.0000263 AC XY: 19AN XY: 721572
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 23, 2020 | Variant summary: APC c.646-8T>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249338 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.646-8T>A has been reported in the literature in at least one individual affected with colorectal cancer (e.g. Yurgelun_2017). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. These laboratories cited the variant as likely benign (n=1) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Classic or attenuated familial adenomatous polyposis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This variant causes a T to A nucleotide substitution at the -8 position of intron 6 of the APC gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with colorectal cancer (PMID: 28135145). This variant has been identified in 1/31380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 11, 2024 | In silico analysis supports that this variant does not alter splicing; Observed in at least one individual with a personal history of colon cancer who underwent multi-gene panel testing (PMID: 28135145); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS5-8T>A; This variant is associated with the following publications: (PMID: 28135145) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 01, 2023 | This variant causes a T to A nucleotide substitution at the -8 position of intron 6 of the APC gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with colorectal cancer (PMID: 28135145). This variant has been identified in 1/31380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Familial adenomatous polyposis 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at