chr5-112840500-G-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. BP2BP1PM2_SupportingBS2
This summary comes from the ClinGen Evidence Repository: The c.4906G>T variant in APC is a missense variant predicted to cause the substitution of aspartate by tyrosine at amino acid position 1636 (p.Asp1636Tyr). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in trans with the variant c.3100G>T (p.Glu1034*) (Bonn internal data) which is classified as Pathogenic by the HCCP VCEP in an individual with FAP (BP2). This variant has been observed in heterozygous state in 11 unrelated healthy adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, although there are both pathogenic and benign types of evidence for this variant, the pathogenic/benign evidence is not considered inconsistent with the final Likely Benign classification for FAP. ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2, BP1, and BP2 (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA009798/MONDO:0021056/089
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.4906G>T | p.Asp1636Tyr | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.4906G>T | p.Asp1636Tyr | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461866Hom.: 0 Cov.: 66 AF XY: 0.00000550 AC XY: 4AN XY: 727238
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 17, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Likely benign, reviewed by expert panel | curation | ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel | Feb 26, 2023 | The c.4906G>T variant in APC is a missense variant predicted to cause the substitution of aspartate by tyrosine at amino acid position 1636 (p.Asp1636Tyr). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in trans with the variant c.3100G>T (p.Glu1034*) (Bonn internal data) which is classified as Pathogenic by the HCCP VCEP in an individual with FAP (BP2). This variant has been observed in heterozygous state in 11 unrelated healthy adult individuals worth more than 10 healthy individual points in total (BS2; Ambry Genetics internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, although there are both pathogenic and benign types of evidence for this variant, the pathogenic/benign evidence is not considered inconsistent with the final Likely Benign classification for FAP. ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2, BP1, and BP2 (VCEP specifications version 1; date of approval: 12/12/2022). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1636 of the APC protein (p.Asp1636Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 183069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 28, 2016 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 22, 2023 | The p.D1636Y variant (also known as c.4906G>T), located in coding exon 15 of the APC gene, results from a G to T substitution at nucleotide position 4906. The aspartic acid at codon 1636 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 11, 2023 | This missense variant replaces aspartic acid with tyrosine at codon 1636 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has not been identified 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 25, 2016 | This variant is denoted APC c.4906G>T at the cDNA level, p.Asp1636Tyr (D1636Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asp1636Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Asp1636Tyr occurs at a position where amino acids with properties similar to Aspartic Acid are tolerated across species and is located in the SAMP repeats/axin binding domain and within a Beta-catenin down-regulating domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Asp1636Tyr is pathogenic or benign. We consider it to be a variant of 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 | Dec 01, 2023 | This missense variant replaces aspartic acid with tyrosine at codon 1636 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. - |
APC-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 04, 2023 | The APC c.4906G>T variant is predicted to result in the amino acid substitution p.Asp1636Tyr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/183069/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at