Submissions for variant NM_000038.6(APC):c.1462C>T (p.Leu488Phe)

dbSNP: rs587779782

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766427	SCV000148978	uncertain significance	not provided	2020-11-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast cancer (Tung 2015); This variant is associated with the following publications: (PMID: 25186627)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003474708	SCV000552463	uncertain significance	Familial adenomatous polyposis 1	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 488 of the APC protein (p.Leu488Phe). This variant is present in population databases (rs587779782, gnomAD 0.0009%). 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: 127277). 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.
Ambry Genetics	RCV000574797	SCV000667281	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-10	criteria provided, single submitter	clinical testing	The p.L488F variant (also known as c.1462C>T), located in coding exon 11 of the APC gene, results from a C to T substitution at nucleotide position 1462. The leucine at codon 488 is replaced by phenylalanine, an amino acid with highly 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000574797	SCV000681464	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 488 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 been identified in 1/251176 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000115069	SCV000731361	uncertain significance	not specified	2017-01-12	criteria provided, single submitter	clinical testing	The p.Leu488Phe variant in APC has not been previously reported in individuals w ith APC-associated polyposis or in large population studies. Computational predi ction tools and conservation analysis do not provide strong support for or again st an impact to the protein. In summary, the clinical significance of the p.Leu4 88Phe variant is uncertain.
Sema4, Sema4	RCV000574797	SCV002528076	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-25	criteria provided, single submitter	curation
Baylor Genetics	RCV003474708	SCV004201971	uncertain significance	Familial adenomatous polyposis 1	2023-08-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997210	SCV004837405	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 488 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has also been identified in 1/251176 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.
Fulgent Genetics, Fulgent Genetics	RCV005031601	SCV005667822	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2024-06-18	criteria provided, single submitter	clinical testing