ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1286C>T (p.Pro429Leu) (rs1003390887)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474960 SCV000552560 uncertain significance Familial adenomatous polyposis 1 2018-03-04 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 429 of the APC protein (p.Pro429Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411413). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000519043 SCV000616638 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing This variant is denoted APC c.1286C>T at the cDNA level, p.Pro429Leu (P429L) at the protein level,and results in the change of a Proline to a Leucine (CCA>CTA). This variant has not, to our knowledge, beenpublished in the literature as pathogenic or benign. APC Pro429Leu was not observed in large population cohorts(NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Leucinediffer in some properties, this is considered a semi-conservative amino acid substitution. APC Pro429Leu occurs at aposition that is not conserved and is not located in a known functional domain. In silico analyses are inconsistentregarding the effect this variant may have on protein structure and function. Based on currently available evidence, it isunclear whether APC Pro429Leu is a pathogenic or benign variant. We consider it to be a variant of uncertainsignificance.
Ambry Genetics RCV000561404 SCV000667702 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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