9-21971117-G-C

Position:

• chr9-21971117-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000077.5(CDKN2A):​c.242C>G​(p.Pro81Arg) variant causes a missense change. 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. P81T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.60

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]

CDKN2A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-21971118-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 9-21971117-G-C is Pathogenic according to our data. Variant chr9-21971117-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 463492.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.242C>G	p.Pro81Arg	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.285C>G	p.Thr95Thr	synonymous_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.242C>G	p.Pro81Arg	missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.285C>G	p.Thr95Thr	synonymous_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 07, 2021	This missense variant replaces proline with arginine at codon 81 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). To our knowledge, functional studies have not been reported for this variant. Other variants at this codon have been observed to be defective for CDK4 binding (PMID: 10389768, 20340136). This variant has been reported in individuals affected with melanoma and pancreatic cancer (PMID: 18023021, 26800492, 26907448, 27804060). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 07, 2021	The p.P81R pathogenic mutation (also known as c.242C>G), located in coding exon 2 of the CDKN2A gene, results from a C to G substitution at nucleotide position 242. The proline at codon 81 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in multiple cohorts of high-risk melanoma patients who either had multiple primary malignant melanomas and/or a family history of malignant melanoma as well as a pancreatic cancer patient (Helsing P et al. Genes Chromosomes Cancer, 2008 Feb;47:175-84; Müller C et al. Br. J. Dermatol., 2016 Jun;174:1308-17; Levin T et al. Fam. Cancer, 2017 Apr;16:257-265; Mantripragada KC et al. J Oncol Pract, 2016 Apr;12:e396-404). This alteration segregates with melanoma and pancreatic cancer in multiple individuals from multiple families (Levin T et al. Fam. Cancer, 2017 Apr;16:257-265; Ambry internal data). Based on internal structural analysis, this alteration lies within a mutational hotspot and will destabilize local structure of the binding interface leading to significantly impaired binding to CDK4 and CDK6 (Ambry internal data; Russo AA et al. Nature, 1998 Sep;395:237-43). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2023

Identified in individuals with multiple primary melanomas, segregating with disease in relatives affected with melanoma or pancreatic cancer (Helsing et al., 2008; Levin et al., 2016; Muller et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21462282, 18023021, 9751050, 19260062, 26800492, 26907448, 27804060) -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 24, 2021

This sequence change replaces proline with arginine at codon 81 of the CDKN2A (p16INK4a) protein (p.Pro81Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with melanoma and multiple primary melanoma (PMID: 18023021, 21462282, 26800492, 19260062, 27804060). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;T;.;.;.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.2	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0050	D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.93
MutPred		0.80		Gain of catalytic residue at P81 (P = 0.0179);Gain of catalytic residue at P81 (P = 0.0179);.;Gain of catalytic residue at P81 (P = 0.0179);.;.;.;.;
MVP		1.0
MPC		1.3
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.86
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs11552823; hg19: chr9-21971116; COSMIC: COSV58717232; COSMIC: COSV58717232;