Submissions for variant NM_000038.6(APC):c.4295C>T (p.Pro1432Leu)

dbSNP: rs1765644448

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004570290	SCV001233152	uncertain significance	Familial adenomatous polyposis 1	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1432 of the APC protein (p.Pro1432Leu). 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: 861517). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Color Diagnostics, LLC DBA Color Health	RCV001525561	SCV001735717	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1432 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 APC-related disorders 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.
Ambry Genetics	RCV001525561	SCV002631063	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-18	criteria provided, single submitter	clinical testing	The p.P1432L variant (also known as c.4295C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 4295. The proline at codon 1432 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV004000171	SCV004837906	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1432 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 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.
PreventionGenetics, part of Exact Sciences	RCV004726863	SCV005336681	uncertain significance	APC-related disorder	2024-04-17	no assertion criteria provided	clinical testing	The APC c.4295C>T variant is predicted to result in the amino acid substitution p.Pro1432Leu. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant has been reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/861517/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.