Submissions for variant NM_000038.6(APC):c.2786A>C (p.His929Pro)

dbSNP: rs730881242

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159543	SCV000209506	uncertain significance	not provided	2014-09-08	criteria provided, single submitter	clinical testing	This variant is denoted APC c.2786A>C at the cDNA level, p.His929Pro (H929P) at the protein level, and results in the change of a Histidine to a Proline (CAT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC His929Pro 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 Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC His929Pro occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC His929Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001804882	SCV002051956	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 929 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 1/250864 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	RCV003534404	SCV002191727	uncertain significance	Familial adenomatous polyposis 1	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 929 of the APC protein (p.His929Pro). This variant is present in population databases (rs730881242, gnomAD 0.003%). 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: 181796). 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	RCV001804882	SCV003866267	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-27	criteria provided, single submitter	clinical testing	The p.H929P variant (also known as c.2786A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 2786. The histidine at codon 929 is replaced by proline, an amino acid with similar properties. 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.