Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV004563360 | SCV000768022 | uncertain significance | Familial adenomatous polyposis 1 | 2024-03-14 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1488 of the APC protein (p.Leu1488Val). This variant is present in population databases (rs765730576, gnomAD 0.0009%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 28726808). ClinVar contains an entry for this variant (Variation ID: 537411). 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 | RCV001022520 | SCV001184270 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-23 | criteria provided, single submitter | clinical testing | The p.L1488V variant (also known as c.4462T>G), located in coding exon 15 of the APC gene, results from a T to G substitution at nucleotide position 4462. The leucine at codon 1488 is replaced by valine, an amino acid with highly similar properties. This variant was identified in 1/302 patients with a previous diagnoses of pancreatic ductal adenocarcinoma and a family history positive for pancreatic cancer (Chaffee KG et al. Genet. Med., 2018 01;20:119-127). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001797771 | SCV002041501 | uncertain significance | not specified | 2021-11-22 | criteria provided, single submitter | clinical testing | Variant summary: APC c.4462T>G (p.Leu1488Val) results in a conservative amino acid change located in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250658 control chromosomes (gnomAD), however the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4462T>G has been reported in the literature in one individual affected with Familial Pancreatic Cancer (Chaffee_2018). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |