9-21971153-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BS2

The NM_000077.5(CDKN2A):c.206A>G(p.Glu69Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000042 in 1,593,674 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E69D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8

Conservation

PhyloP100: 5.68

Publications

17 publications found

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]

CDKN2A Gene-Disease associations (from GenCC):

melanoma, cutaneous malignant, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
melanoma-pancreatic cancer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial atypical multiple mole melanoma syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
melanoma and neural system tumor syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CDKN2A links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 41 uncertain in NM_000077.5

BS2

High AC in GnomAdExome4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5 link	c.206A>G	p.Glu69Gly	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4 link	c.249A>G	p.Gly83Gly	synonymous_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 link	c.206A>G	p.Glu69Gly	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2 link	c.249A>G	p.Gly83Gly	synonymous_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000945

AC:

AN:

211552

AF XY:

0.00000847

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000213

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000437

AC:

AN:

1441668

Hom.:

Cov.:

AF XY:

0.0000460

AC XY:

AN XY:

717202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33246

American (AMR)

AF:

0.00

AC:

AN:

43906

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25956

East Asian (EAS)

AF:

0.00

AC:

AN:

39218

South Asian (SAS)

AF:

0.00

AC:

AN:

85448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5368

European-Non Finnish (NFE)

AF:

0.0000559

AC:

AN:

1108818

Other (OTH)

AF:

0.0000167

AC:

AN:

59820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67966

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000426

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.00000840

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Feb 03, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with glycine at codon 69 of the CDKN2A protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown the mutant protein to exhibit reduced binding to CDK4 and/or CDK6 (PMID: 19260062, 20340136); however, cell proliferation and cell cycle progression assays showed activity comparable to wild-type (PMID: 35001868). This variant has been reported in individuals affected with melanoma (PMID: 17047042, 19484507, 21325014, 21462282, 24660985, 25780468), colorectal cancer (PMID: 25980754, 28135145), and breast cancer (PMID: 33753322). However, the variant did not show segregation with melanoma in multiple families; the variant was observed in unaffected individuals (PMID: 21462282) and was absent in some affected individuals (PMID: 19260062). This variant has been observed together with pathogenic BRCA2 variants in two unrelated families and with a pathogenic CHEK2 variant in a family with a history of melanoma and prostate cancer (Color internal data). This variant has been identified in 2/211552 chromosomes 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. -

Dec 02, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E69G variant (also known as c.206A>G), located in coding exon 2 of the CDKN2A gene, results from an A to G substitution at nucleotide position 206 of the p16 protein-encoding isoform. The glutamic acid at codon 69 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in multiple individuals diagnosed with melanoma; however, it did not segregate completely with disease (Goldstein AM et al. Cancer Res. 2006 Oct; 66(20):9818-28; Harland M et al. Hered Cancer Clin Pract 2014;12(1):20; Kannengiesser C et al. Hum. Mutat. 2009 Apr; 30(4):564-74; Hatvani Z et al. Exp. Dermatol. 2014 May;23(5):361-4; Cust AE et al. J. Med. Genet., 2011 Apr;48:266-72; Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11; Chaudru V et al. Fam. Cancer, 2009 May;8:371-7). This variant showed increased growth as well as decreased binding to both CDK6 and CDK4, although the CDK4 binding defect may be intermediate with respect to other known pathogenic CDKN2A missense mutations (Kannengiesser C et al. Hum. Mutat. 2009 Apr; 30(4):564-74; McKenzie HA et al. Hum. Mutat. 2010 Jun; 31(6):692-701). Another functional study reported this variant as neutral based on in-vitro assessment of impact on proliferation in human pancreatic cancer cell lines (Kimura H et al. Elife, 2022 01;11:). Based on internal structural analysis, this amino acid lies within the probable CDK4 binding site and is in close contact with other amino acids at which other pathogenic missense substitutions are found; however the change from glutamic acid to glycine is predicted to only mildly destabilize local structure and protein-protein binding interactions (Ambry internal data; Kannengiesser C et al. Hum. Mutat. 2009 Apr; 30(4):564-74; Russo AA et al. Nature, 1998 Sep;395:237-43). Based on the majority of available evidence to date, this variant is likely to be pathogenic with moderate risk. -

not specified

Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CDKN2A c.206A>G (p.Glu69Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 1593674 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma (4.2e-05 vs 0.0003), allowing no conclusion about variant significance. The variant, c.206A>G, has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Chandru_2009, Cust_2011, Goldstein_2006, Hatvani_2014, Miller_2011). The variant has been found to lack co-segregation with disease being observed in unaffected individuals, along with being absent from affected individuals (Kannengiesser_2009, Miller_2011). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Co-occurrence with another pathogenic variant has been reported (MLH1 c.589-2A>G) (Yurgelun_2015), providing supporting evidence for a benign role. Functional studies report the variant affects CDK4 and CDK6 binding ability, Ki67 index and cellular locatization of p16 protein (McKenzie_2010, Kannengiesser_2009). The following publications have been ascertained in the context of this evaluation (PMID: 21462282, 25980754, 25780468, 20340136, 21325014, 17047042, 26104880, 19260062, 28135145, 19484507, 24660985, 30303537, 30709382, 35001868). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Melanoma and neural system tumor syndrome

Uncertain:1

Mar 27, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Feb 19, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies are inconclusive: reduced CDK4 and CDK6 binding ability but no effect on cell proliferation (PMID: 19260062, 20340136, 35001868); Observed in individuals and families with CDKN2A-related cancers (PMID: 17047042, 16905682, 19260062, 25780468, 24660985); 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: 25780468, 17047042, 21325014, 26104880, 9425228, 25980754, 20340136, 19260062, 24660985, 21462282, 20876876, 16905682, 19484507, 28135145, 30709382, 35001868, 33753322, 29922827, 39821174) -

Melanoma-pancreatic cancer syndrome

Uncertain:1

Aug 14, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome

Uncertain:1

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial melanoma

Uncertain:1

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 69 of the CDKN2A (p16INK4a) protein (p.Glu69Gly). This variant is present in population databases (rs372670098, gnomAD 0.002%). This missense change has been observed in individual(s) with melanoma (PMID: 17047042, 21325014, 24660985). ClinVar contains an entry for this variant (Variation ID: 186615). 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 tolerated. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 19260062, 20340136). 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;.;.;.;.;T;.

Eigen

Benign

0.029

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;T;.;D;.;T;T;T

M_CAP

Pathogenic

0.43

MetaRNN

Uncertain

0.47

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

PhyloP100

5.7

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.3

D;.;.;D;.;.;.;.

REVEL

Uncertain

0.39

Sift

Uncertain

0.0060

D;.;.;D;.;.;.;.

Sift4G

Uncertain

0.020

D;D;D;D;D;D;D;D

Polyphen

0.40

B;.;.;.;.;.;.;.

Vest4

0.26

MVP

0.98

MPC

0.97

ClinPred

0.86

GERP RS

5.8

PromoterAI

0.032

Neutral

(source)

Varity_R

0.22

gMVP

0.80

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over