ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7720C>A (p.Leu2574Ile)

gnomAD frequency: 0.00001  dbSNP: rs876659753
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217741 SCV000276553 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-03 criteria provided, single submitter clinical testing The p.L2574I variant (also known as c.7720C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 7720. The leucine at codon 2574 is replaced by isoleucine, an amino acid with highly similar properties. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this variant remains unclear.
Mendelics RCV000987586 SCV001136948 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000987586 SCV003026928 uncertain significance Familial adenomatous polyposis 1 2024-08-01 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2574 of the APC protein (p.Leu2574Ile). 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: 232420). 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.
Color Diagnostics, LLC DBA Color Health RCV000217741 SCV006061230 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-04 criteria provided, single submitter clinical testing This missense variant replaces leucine with isoleucine at codon 2574 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 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.

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