rs121913385
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_000077.5(CDKN2A):c.247C>T(p.His83Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H83D) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CDKN2A
NM_000077.5 missense
NM_000077.5 missense
Scores
6
4
3
Clinical Significance
Conservation
PhyloP100: 9.23
Genes affected
CDKN2A (HGNC:1787): (cyclin dependent kinase inhibitor 2A) This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000077.5
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr9-21971110-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 376381.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.247C>T | p.His83Tyr | missense_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.290C>T | p.Ala97Val | missense_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.247C>T | p.His83Tyr | missense_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.290C>T | p.Ala97Val | missense_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1451924Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 722664
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1451924
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
722664
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:10Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Squamous cell carcinoma of the skin Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Pancreatic adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Melanoma-pancreatic cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 08, 2023 | 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]. - |
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant melanoma of skin Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the head and neck Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Melanoma and neural system tumor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 26, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 11, 2023 | 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. - |
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Benign
T;T
Vest4
MVP
ClinPred
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at