Submissions for variant NM_000038.6(APC):c.911T>C (p.Leu304Pro)

gnomAD frequency: 0.00001  dbSNP: rs1064793322

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482238	SCV000565800	uncertain significance	not provided	2016-10-13	criteria provided, single submitter	clinical testing	This variant is denoted APC c.911T>C at the cDNA level, p.Leu304Pro (L304P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant was observed in at least one individual undergoing clinical evaluation for Familial Adenomatous Polyposis (Kerr 2013). APC Leu304Pro 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 Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. APC Leu304Pro occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is not located in a known functional domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Leu304Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000570748	SCV000667369	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	The p.L304P variant (also known as c.911T>C), located in coding exon 8 of the APC gene, results from a T to C substitution at nucleotide position 911. The leucine at codon 304 is replaced by proline, an amino acid with similar properties. This alteration was detected in a cohort of 1591 individuals referred to the Mayo Clinic for full APC genetic testing, however the clinical information for these individuals was not published (Kerr SE et al. J Mol Diagn. 2013 Jan; 15(1):31-43). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000570748	SCV000681936	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-17	criteria provided, single submitter	clinical testing
Invitae	RCV002525774	SCV000768096	uncertain significance	Familial adenomatous polyposis 1	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 304 of the APC protein (p.Leu304Pro). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with familial adenomatous polyposis (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 418609). 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482238	SCV001133380	uncertain significance	not provided	2018-11-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000570748	SCV002529563	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-26	criteria provided, single submitter	curation