ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.315C>A (p.Asp105Glu) (rs763269347)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467808 SCV000545515 uncertain significance Hereditary melanoma 2020-09-18 criteria provided, single submitter clinical testing The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. This sequence change replaces aspartic acid with glutamic acid at codon 105 of the CDKN2A (p16INK4a) protein (p.Asp105Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. Alternatively, this sequence change replaces arginine with serine at codon 120 of the CDKN2A (p14ARF) protein (p.Arg120Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs763269347, ExAC 0.04%). This variant has been reported in an individual with melanoma (PMID: 10229204). ClinVar contains an entry for this variant (Variation ID: 406702). 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.
Ambry Genetics RCV000569825 SCV000669195 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-21 criteria provided, single submitter clinical testing The p.D105E variant (also known as c.315C>A), located in coding exon 2 of the CDKN2A gene, results from a C to A substitution at nucleotide position 315. The aspartic acid at codon 105 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in the germline of an individual with sporadic cutaneous melanoma (Fujimoto A et al. Oncogene. 1999 Apr;18:2527-32). This amino acid position is well 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 Health, Inc RCV000569825 SCV000684521 likely benign Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing
Counsyl RCV000663166 SCV000786326 uncertain significance Melanoma-pancreatic cancer syndrome 2018-04-11 criteria provided, single submitter clinical testing
Mendelics RCV000709066 SCV000838326 uncertain significance Cutaneous malignant melanoma 2 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000663166 SCV001137763 uncertain significance Melanoma-pancreatic cancer syndrome 2019-05-28 criteria provided, single submitter clinical testing

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