Submissions for variant NM_000038.6(APC):c.8135C>T (p.Pro2712Leu)

gnomAD frequency: 0.00001  dbSNP: rs1269106823

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003535924	SCV000941607	uncertain significance	Familial adenomatous polyposis 1	2023-09-04	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 647323). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2712 of the APC protein (p.Pro2712Leu).
Ambry Genetics	RCV001027211	SCV001189729	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-16	criteria provided, single submitter	clinical testing	The p.P2712L variant (also known as c.8135C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 8135. The proline at codon 2712 is replaced by leucine, an amino acid with 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.
GeneDx	RCV001776015	SCV002012938	uncertain significance	not provided	2020-01-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV002534689	SCV004201624	uncertain significance	Familial adenomatous polyposis 1	2023-07-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001027211	SCV004358592	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 2712 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 APC-related disorders in the literature. This variant has been identified in 2/251324 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.