Submissions for variant NM_000038.6(APC):c.1435T>A (p.Leu479Met)

gnomAD frequency: 0.00001  dbSNP: rs780577693

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561344	SCV000675887	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	The p.L479M variant (also known as c.1435T>A), located in coding exon 11 of the APC gene, results from a T to A substitution at nucleotide position 1435. The leucine at codon 479 is replaced by methionine, 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	RCV000561344	SCV000681460	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 479 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 3/251146 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004562487	SCV000825807	uncertain significance	Familial adenomatous polyposis 1	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 479 of the APC protein (p.Leu479Met). This variant is present in population databases (rs780577693, 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: 486746). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196154	SCV001366675	uncertain significance	Colorectal cancer	2019-05-23	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1.
All of Us Research Program, National Institutes of Health	RCV004001185	SCV004837398	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 479 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251146 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.