ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8286C>A (p.Phe2762Leu)

gnomAD frequency: 0.00002  dbSNP: rs879254185
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235534 SCV000293748 uncertain significance not provided 2015-12-26 criteria provided, single submitter clinical testing This variant is denoted APC c.8286C>A at the cDNA level, p.Phe2762Leu (F2762L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Phe2762Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. APC Phe2762Leu occurs at a position that is conserved across species and is located in the EB1 binding domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Phe2762Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV004563279 SCV000824677 uncertain significance Familial adenomatous polyposis 1 2024-12-23 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2762 of the APC protein (p.Phe2762Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 246268). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics RCV002429154 SCV002677240 uncertain significance Hereditary cancer-predisposing syndrome 2022-07-17 criteria provided, single submitter clinical testing The p.F2762L variant (also known as c.8286C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 8286. The phenylalanine at codon 2762 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. 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.

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