Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000638983 | SCV000760541 | uncertain significance | Familial melanoma | 2023-11-24 | criteria provided, single submitter | clinical testing | 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. This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 83 of the CDKN2A (p16INK4a) protein (p.His83Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with sporadic and multiple primary melanomas (PMID: 16234564, 16896043, 21462282). This variant is also known as c.290C>T (p.Ala97Val) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 376307). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 7780957, 8521414, 9324288, 10491434). 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 | RCV002446641 | SCV002735394 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-11 | criteria provided, single submitter | clinical testing | The p.H83Y variant (also known as c.247C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 247. The histidine at codon 83 is replaced by tyrosine, an amino acid with similar properties. This alteration was identified in cohorts with sporadic and multiple melanomas (Begg CB et al. J Natl Cancer Inst, 2005 Oct;97:1507-15; Miller PJ et al. Hum Mutat, 2011 Aug;32:900-11). Protein functional studies have shown this variant to have inhibited CDK4 and CDK6 binding and to have increased proliferation activity compared to wild-type (Yang R et al. Cancer Res, 1995 Jun;55:2503-6; Gombart AF et al. Leukemia, 1997 Oct;11:1673-80; Yarbrough WG et al. J Natl Cancer Inst, 1999 Sep;91:1569-74). This amino acid position is highly 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. |
Myriad Genetics, |
RCV003316521 | SCV004020160 | likely pathogenic | Melanoma-pancreatic cancer syndrome | 2023-03-08 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 35001868, 9324288]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21462282, 16234564]. |
Baylor Genetics | RCV003476006 | SCV004212517 | uncertain significance | Melanoma and neural system tumor syndrome | 2023-05-26 | criteria provided, single submitter | clinical testing | |
Database of Curated Mutations |
RCV000426295 | SCV000505633 | likely pathogenic | Neoplasm | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439424 | SCV000505866 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419112 | SCV000505867 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429387 | SCV000505868 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438754 | SCV000505869 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421013 | SCV000505870 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432117 | SCV000505871 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438919 | SCV000505872 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423848 | SCV000505873 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only |