ClinVar Miner

Submissions for variant NM_001363763.2(CDKN2A):c.-4+591G>A

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV001090490 SCV001246068 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Invitae RCV001378150 SCV001575651 likely pathogenic Hereditary melanoma 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp34*) in the CDKN2A (p14ARF) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the CDKN2A (p14ARF) protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with melanoma (PMID: 25780468). ClinVar contains an entry for this variant (Variation ID: 870835). This variant disrupts the nucleolar localization domain of the CDKN2A (p14ARF) protein, which is required for its nucleolar targeting (PMID: 10871849). This variant also disrupts the Topo interaction domain of the CDKN2A (p14ARF) protein, which is required for its binding with topoisomerase I (Topo I) (PMID: 12673200). While functional studies have not been performed to directly test the effect of this variant on CDKN2A (p14ARF) protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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