Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000160409 | SCV000210942 | pathogenic | Hereditary cancer-predisposing syndrome | 2014-05-15 | criteria provided, single submitter | clinical testing | This variant is denoted c.339_340delGCinsCT at the cDNA level and p.Pro114Ser (P114S) at the protein level. The normal sequence with the bases that are deleted in braces followed by the inserted bases in brackets is: GTCT{delGC}[insCT]CCGT. The c.339_340delGCinsCT mutation in the CDKN2A gene has been reported previously in associationwith familial cutaneous malignant melanoma (Goldstein et al., 2006; Kannengeisser et al., 2007), and functional studies have shown that the resulting mutatnt protein has significantly reduced binding to CDK4 (Kannengeisser et al., 2009). The insertion and deletion result in the synonymous replacement of the normal Leucine codon (CTG) with a different Leucine codon (CTC) at amino acid position 113, and in the replacement of a Proline codon (CCC) with a Serine codon (TCC) at amino acid position 114. The NHLBI ESP Exome Variant Server reports c.339_340delGCinsCT was not observed in approximately 6,400 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, weinterpret c.339_340delGCinsCT as a disease-causing mutation. The variant is found in CDKN2A panel(s). |
| Labcorp Genetics |
RCV001851778 | SCV002291656 | uncertain significance | Familial melanoma | 2022-02-24 | criteria provided, single submitter | clinical testing | 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 9053859, 19260062, 23190892, 24659262). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 9424). This variant is also known as c.382_383delinsCT (p.Ala128Leu) in the CDKN2A (p14ARF) transcript. This missense change has been observed in individual(s) with melanoma (PMID: 17492760, 17992122, 21462282). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 114 of the CDKN2A (p16INK4a) protein (p.Pro114Ser). The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. |
| OMIM | RCV000010031 | SCV000030252 | risk factor | Melanoma, cutaneous malignant, susceptibility to, 2 | 2007-08-01 | no assertion criteria provided | literature only |