Submissions for variant NM_000038.6(APC):c.3970C>G (p.Pro1324Ala)

dbSNP: rs587779792

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115089	SCV000148998	uncertain significance	not provided	2013-10-17	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3970C>G at the cDNA level, p.Pro1324Ala (P1324A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Pro1324Ala 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. This variant is a semi-conservative substitution of a neutral non-polar amino acid for a neutral non-polar one, altering a position that is well conserved throughout evolution and is located in the in a region involved in ubiquitination leading to APC downregulation. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on currently available information, it is unclear whether APC Pro1324Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV003743563	SCV000647484	uncertain significance	Familial adenomatous polyposis 1	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1324 of the APC protein (p.Pro1324Ala). 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: 127292). 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.
Ambry Genetics	RCV001021555	SCV001183183	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-22	criteria provided, single submitter	clinical testing	The p.P1324A variant (also known as c.3970C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 3970. The proline at codon 1324 is replaced by alanine, an amino acid with highly similar 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.
Color Diagnostics, LLC DBA Color Health	RCV001021555	SCV001347423	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 1324 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Sema4, Sema4	RCV001021555	SCV002536226	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-12	criteria provided, single submitter	curation