Submissions for variant NM_000038.6(APC):c.4993C>G (p.Pro1665Ala)

dbSNP: rs1561596883

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003535964	SCV000946332	uncertain significance	Familial adenomatous polyposis 1	2023-04-27	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: 651065). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1665 of the APC protein (p.Pro1665Ala).
Color Diagnostics, LLC DBA Color Health	RCV001185620	SCV001351871	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-18	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 1665 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 been identified in 1/250332 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.
Ambry Genetics	RCV001185620	SCV002642303	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-05	criteria provided, single submitter	clinical testing	The p.P1665A variant (also known as c.4993C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 4993. The proline at codon 1665 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. 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.
Genetic Services Laboratory, University of Chicago	RCV003151152	SCV003839759	uncertain significance	not specified	2022-05-26	no assertion criteria provided	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.4993C>G, in exon 16 that results in an amino acid change, p.Pro1665Ala. This sequence change does not appear to have been previously described in individuals with APC-related disorders. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0004 % (dbSNP NA). The p.Pro1665Ala change affects a highly conserved amino acid residue located in a domain of the APC protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro1665Ala substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro1665Ala change remains unknown at this time.