rs749714198
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM5PP5_Very_StrongBP4
The NM_000077.5(CDKN2A):c.259C>T(p.Arg87Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,604,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R87P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000077.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.259C>T | p.Arg87Trp | missense_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.302C>T | p.Pro101Leu | missense_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.259C>T | p.Arg87Trp | missense_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.302C>T | p.Pro101Leu | missense_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000861 AC: 2AN: 232208Hom.: 0 AF XY: 0.0000156 AC XY: 2AN XY: 127986
GnomAD4 exome AF: 0.00000344 AC: 5AN: 1452390Hom.: 0 Cov.: 31 AF XY: 0.00000692 AC XY: 5AN XY: 722914
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74380
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 12, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17370310, 21462282, 10874641, 21801156, 27804060, 25780468, 26650572, 25685612, 18023021, 26681309, 30218143, 35001868, Andreev2022[FunctionalStudy], 23190892, Jang2022[CaseReport], 19260062, 15860862, 31567591, 29774366, 33237286) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2024 | The p.R87W variant (also known as c.259C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 259. The arginine at codon 87 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with sporadic melanoma, multiple melanomas, and/or familial melanoma (Ambry internal data; Ruiz A et al. J Med Genet. 1999 Jun;36(6):490-3; Puig S et al. J Clin Oncol. 2005 May 1;23(13):3043-51; Helsing P et al. Genes Chromosomes Cancer. 2008 Feb;47(2):175-84; Cuellar F et al. Br J Dermatol. 2009 Jan;160(1):48-53; Kannengiesser C et al. Hum Mutat. 2009 Apr;30(4):564-74; Nikolaou V et al. Br J Dermatol. 2011 Dec;165(6):1219-22; Di Lorenzo S et al. Cancer Biol Ther. 2016;17(1):83-90; Li C et al. Melanoma Res 2020 06;30(3):247-251). Although a CDK4 binding assay showed only partial loss of CDK4 binding activity, a proliferation assay showed impaired capacity to inhibit proliferation of human diploid fibroblasts (Kannengiesser C et al. Hum Mutat. 2009 Apr;30(4):564-74). Additional functional assays have shown partial activity in a cell cycle arrest assay and impaired capacity to regulate both oxidative stress and cell cycle regulatory activity (Miller PJ et al. Hum Mutat. 2011 Aug;32(8):900-11; Jenkins NC et al. J Invest Dermatol. 2013 Apr;133(4):1043-51). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 25, 2020 | This missense variant replaces arginine with tryptophan at codon 87 in the ankyrin repeat 3 of the CDKN2A (p16INK4A) protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes a partial reduction in CDK4 binding (PMID: 19260062) and a significant loss of ability to control cell cycle (PMID: 19260062, 21462282, 23190892). This variant has been reported in at least twenty individuals affected with melanoma (PMID: 10874641, 15860862, 18023021, 19260062, 21462282, 21801156, 26650572) and in an unaffected individual (PMID: 26650572). This variant has been identified in 2/232208 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Melanoma and neural system tumor syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 27, 2023 | - - |
Melanoma-pancreatic cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Familial melanoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 87 of the CDKN2A (p16INK4a) protein (p.Arg87Trp). This variant is present in population databases (rs749714198, gnomAD 0.003%). This missense change has been observed in individual(s) with familial melanoma (PMID: 10874641, 15860862, 18023021, 19260062, 21462282, 26650572, 26681309, 29774366). It has also been observed to segregate with disease in related individuals. This variant is also known as c.302C>T (p.Pro101Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 406707). 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: 19260062, 21462282, 23190892). 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: 7647780, 7987387, 8603820, 12352668). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic. In the absence of additional clinical evidence, this variant has been classified as Likely Pathogenic. While this evidence indicates that the variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, the association of this variant with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at