9-21971093-C-T

Position:

• chr9-21971093-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.266G>A​(p.Gly89Asp) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G89G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 O:1
• Conservation: PhyloP100: 7.31

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 16 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, 0.974
• PP5: Variant 9-21971093-C-T is Pathogenic according to our data. Variant chr9-21971093-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21971093-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.266G>A	p.Gly89Asp	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.309G>A	p.Gly103Gly	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.266G>A	p.Gly89Asp	missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.309G>A	p.Gly103Gly	synonymous_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1452624 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 24, 2024	The p.G89D pathogenic mutation (also known as c.266G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 266. The glycine at codon 89 is replaced by aspartic acid, an amino acid with similar properties. Of note, this variant is also known as c.309G>A (p.G103G) in the p14(ARF) isoform. This variant has been reported as a highly penetrant Icelandic founder mutation in the CDKN2A gene with a significantly increased risk of melanoma, head and neck cancers, and pancreatic cancer in carrier families (Goldstein AM et al. J Med Genet. 2008 May;45(5):284-9). In an in vitro cell proliferation assay, this variant was classified as functionally deleterious (Kimura H et al. Elife, 2022 01;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 supporting evidence, this variant is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 27, 2023	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant replaces glycine with aspartic acid at codon 89 of the CDKN2A (p16INK4A) protein. Computational prediction tool 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 that this variant failed to suppress cell proliferation and showed cell cycle changes similar to known pathogenic variants (PMID: 35001868). This variant has been reported in multiple families and individuals affected with melanoma and/or pancreatic cancer (PMID: 18178632, 21462282, 33945383) and is reported to be associated with melanoma in a case-control study (PMID: 18178632). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 12, 2021	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2018	The G89D variant in the CDKN2A gene has been reported as a highly penetrant risk allele which isstrongly associated with increased melanoma risk, and is theorized to be an Icelandic pathogenicfounder variant (Goldstein et al., 2008). The G89D variant was not observed in approximately 6,400individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. This substitution occurs at aposition that is not conserved. However, this position is within the ANK 3 repeat domain (Uniprot).The G89D variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties, and in silicoanalysis predicts this variant is probably damaging to the protein structure/function. Multiple missensevariants in nearby residues have been reported in the Human Gene Mutation Database in associationwith CDKN2A-related disorders (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Based on the currently available evidence, we consider G89D to be pathogenic. -

Melanoma-pancreatic cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 14, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35001868]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18178632, 33945383]. -

Familial melanoma Uncertain:1

Uncertain significance, flagged submission

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 89 of the CDKN2A (p16INK4a) protein (p.Gly89Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with head and neck cancers, melanoma, and/or pancreatic carcinoma (PMID: 18178632; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9426). 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: 35001868). 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. -

Melanoma, cutaneous malignant, susceptibility to, 2 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;T;.;.;.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.6	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;.;.;D;.;.;.;.
Sift4G	Benign	0.071	T;T;D;T;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.87
MutPred		0.86		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;Gain of loop (P = 0.1069);.;.;.;.;
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.90
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs137854599; hg19: chr9-21971092; COSMIC: COSV100448493; COSMIC: COSV100448493;