Submissions for variant NM_000038.6(APC):c.7916A>C (p.Glu2639Ala)

gnomAD frequency: 0.00001  dbSNP: rs778376399

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486703	SCV000567473	uncertain significance	not provided	2015-07-27	criteria provided, single submitter	clinical testing	This variant is denoted APC c.7916A>C at the cDNA level, p.Glu2639Ala (E2639A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Glu2639Ala 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 Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Glu2639Ala occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located in the EB1 binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Glu2639Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000582053	SCV000687153	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 2639 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been identified in 4/282130 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.
Invitae	RCV003651924	SCV000768268	uncertain significance	Familial adenomatous polyposis 1	2023-09-29	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 419575). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (rs778376399, gnomAD 0.002%). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 2639 of the APC protein (p.Glu2639Ala).
Mendelics	RCV000646495	SCV000838158	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000582053	SCV002530955	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
Ambry Genetics	RCV000582053	SCV002677277	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	clinical testing	The p.E2639A variant (also known as c.7916A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 7916. The glutamic acid at codon 2639 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.