Submissions for variant NM_000077.5(CDKN2A):c.260G>C (p.Arg87Pro)

dbSNP: rs878853647

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229122	SCV000283439	pathogenic	Familial melanoma	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 87 of the CDKN2A (p16INK4a) protein (p.Arg87Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma, lung cancer, and head and neck squamous cell carcinoma and melanoma (PMID: 7987387, 12352668). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg79Pro in CDKN2a (p16INK4a) transcript, or c.303G>C (Silent) in CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 236984). 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: 8668202, 10491434, 10498896, 19260062, 21462282). This variant disrupts the p.Arg87 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10874641). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000580515	SCV000684519	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-11	criteria provided, single submitter	clinical testing	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces arginine with proline at codon 87 in the ankyrin repeats domain of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to exhibit almost complete loss of interaction with CDK4 and CDK6 proteins and cell cycle control function (PMID: 8668202, 10491434, 10498896, 19260062, 21462282). This variant has been reported in at least 6 unrelated individuals affected with familial melanoma (PMID: 7987387, 15146471; Color internal data), with two of these families having relatives affected with pancreatic cancer (PMID: 15146471). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same position, p.Arg87Trp, is known to be disease-causing (ClinVar variation ID: 406707), indicating that arginine at this position is functionally important. Based on the available evidence, this variant is classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680454	SCV000807827	pathogenic	Melanoma, cutaneous malignant, susceptibility to, 2	2018-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580515	SCV003995612	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	The p.R87P pathogenic mutation (also known as c.260G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 260. The arginine at codon 87 is replaced by proline, an amino acid with dissimilar properties. This alteration was identified in multiple individuals diagnosed with CDKN2A-associated disease (Ambry internal data; Yu KK et al. Laryngoscope, 2002 Sep;112:1587-93). This alteration showed loss of function in a cell cycle arrest assay (Miller PJ et al. Hum Mutat, 2011 Aug;32:900-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV004567708	SCV005057269	pathogenic	Melanoma and neural system tumor syndrome	2023-11-13	criteria provided, single submitter	clinical testing