rs121913386

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000077.5(CDKN2A):​c.341C>T​(p.Pro114Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. P114S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CDKN2A
NM_000077.5 missense

Scores

12
5
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 9.18
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 42 pathogenic changes around while only 12 benign (78%) in NM_000077.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 9-21971018-G-A is Pathogenic according to our data. Variant chr9-21971018-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 77637.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDKN2ANM_000077.5 linkc.341C>T p.Pro114Leu missense_variant Exon 2 of 3 ENST00000304494.10 NP_000068.1 P42771-1K7PML8
CDKN2ANM_058195.4 linkc.384C>T p.Ala128Ala synonymous_variant Exon 2 of 3 ENST00000579755.2 NP_478102.2 Q8N726-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDKN2AENST00000304494.10 linkc.341C>T p.Pro114Leu missense_variant Exon 2 of 3 1 NM_000077.5 ENSP00000307101.5 P42771-1
CDKN2AENST00000579755.2 linkc.384C>T p.Ala128Ala synonymous_variant Exon 2 of 3 1 NM_058195.4 ENSP00000462950.1 Q8N726-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial melanoma Pathogenic:1Uncertain:1
Feb 11, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline with leucine at codon 114 of the CDKN2A (p16INK4a) protein (p.Pro114Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. 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. This variant has been reported to affect CDKN2A (p16INK4a) protein function (PMID: 7777060, 7777061, 8668202, 9328469, 9053859, 12606942, 21462282). This variant has been observed in several individuals affected with melanoma (PMID: 9856841, 21462282). Segregation studies have not been reported. ClinVar contains an entry for this variant (Variation ID: 77637). This variant is not present in population databases (ExAC no frequency). -

Jan 08, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CDKN2A c.341C>T (p.Pro114Leu) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 239394 control chromosomes (gnomAD). c.341C>T has been reported as a germline mutation in the literature in several individuals affected with familial melanoma (e.g. Fargnoli_1998, Spica_2011, Pellegrini_2019). However, no co-segregation studies have been performed, therefore these data do not allow any definitive conclusion about variant significance. The variant has also been reported numerous times as a somatic mutation in melanomas and other cancers. Multiple publications report experimental evidence evaluating an impact on protein function, indicating that the variant is non-functional and unable to bind Cdk4/Cdk6 or induce G1 cell cycle arrest in-vitro (e.g. Koh_1995, Parry_1996, Byeon_1998, Jiang_1998, Gump_2001, Miller _2011). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as pathogenic and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Malignant tumor of urinary bladder Pathogenic:1
-
Laboratory of Urology, Hospital Clinic de Barcelona
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:1
Jul 22, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P114L variant (also known as c.341C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 341. The proline at codon 114 is replaced by leucine, an amino acid with similar properties. This alteration is non functional in multiple studies including with respect to CDK4/6 binding and cell cycle control (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; Parry and Peters, Mol. Cell. Biol. 1996 Jul;16(7):3844-52; Tevelev A et al. Biochemistry 1996 Jul;35(29):9475-87). This alteration has been observed in multiple individuals who have a personal or family history that is consistent with CDKN2A-associated disease (Ambry internal data; Fargnoli MC et al. J. Invest. Dermatol., 1998 Dec;111:1202-6; 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. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.55
D;T;.;.;.;.;T;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;.;D;.;D;D;D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.18
D
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-9.4
D;.;.;D;.;.;.;.
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0010
D;.;.;D;.;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.;.;.
Vest4
0.94
MutPred
0.89
Gain of MoRF binding (P = 0.061);Gain of MoRF binding (P = 0.061);.;Gain of MoRF binding (P = 0.061);.;.;.;.;
MVP
0.99
MPC
1.2
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.82
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913386; hg19: chr9-21971017; COSMIC: COSV58683051; COSMIC: COSV58683051; API