ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3128C>T (p.Pro1043Leu)

gnomAD frequency: 0.00001  dbSNP: rs1030285956
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484691 SCV000566204 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing This variant is denoted APC c.3128C>T at the cDNA level, p.Pro1043Leu (P1043L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Pro1043Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Pro1043Leu occurs at a position that is conserved across species and is located within 15-amino acid repeat beta-catenin binding domain (Azzopardi 2008). 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 Pro1043Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV003535745 SCV000768061 uncertain significance Familial adenomatous polyposis 1 2024-01-28 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 1043 of the APC protein (p.Pro1043Leu). This variant is present in population databases (no rsID available, 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: 418844). 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 RCV001018744 SCV001180017 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-19 criteria provided, single submitter clinical testing The p.P1043L variant (also known as c.3128C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3128. The proline at codon 1043 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health RCV001018744 SCV002052000 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-24 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 1043 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 1/250686 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003401516 SCV004121781 uncertain significance not specified 2023-10-18 criteria provided, single submitter clinical testing

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