rs786204198

chr9-21974724-C-Gchr9-21974724-C-Achr9-21974724-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_000077.5(CDKN2A):c.104G>C(p.Gly35Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,612,992 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G35E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 2.65

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000077.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 9-21974724-C-G is Pathogenic according to our data. Variant chr9-21974724-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 463481.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=1, Uncertain_significance=2}. Variant chr9-21974724-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.104G>C	p.Gly35Ala	missense_variant	1/3	ENST00000304494.10
CDKN2A	NM_058195.4 linkuse as main transcript	c.194-3516G>C		intron_variant		ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.104G>C	p.Gly35Ala	missense_variant	1/3	1	NM_000077.5	P2	P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.194-3516G>C		intron_variant		1	NM_058195.4		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

244916

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133668

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000274

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1460806

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726730

show subpopulations

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:

0.0000567

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 20, 2021	The p.G35A pathogenic mutation (also known as c.104G>C), located in coding exon 1 of the CDKN2A gene, results from a G to C substitution at nucleotide position 104. The glycine at codon 35 is replaced by alanine, an amino acid with similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with CDKN2A-related disease (Ambry internal data). This alteration has been identified in numerous cutaneous melanoma kindreds and was found to segregate with disease in multiple families (Ambry internal data; Walker GJ et al. Hum. Mol. Genet. 1995 Oct;4:1845-52; Soufir N et al. Hum. Mol. Genet. 1998 Feb;7:209-16; Goldstein AM et al. Cancer Res. 2006 Oct;66:9818-28). It has also been identified in an individual with uveal melanoma (Hearle N et al. Invest. Ophthalmol. Vis. Sci. 2003 Feb;44:458-62). In the majority of functional assays, the p.G35A mutant demonstrates partially deficient CDK4 binding ability, cellular localization, and cell proliferation (Ghiorzo P et al. Hum. Pathol. 2004 Jan;35:25-33; Kannengiesser C et al. Hum. Mutat. 2009 Apr;30:564-74; McKenzie HA et al. Hum. Mutat. 2010 Jun;31:692-701; Scaini MC et al. Hum. Mutat. 2014 Jul;35:828-40); however, in oxidative function and cell cycle assays, p.G35A retained wild type function (Jenkins NC et al. J. Invest. Dermatol. 2013 Apr;133:1043-51). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry Internal Data; Byeon IJ et al. Mol Cell 1998 Feb;1(3):421-31). 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 10, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 21, 2023	This missense variant replaces glycine with alanine at codon 35 in the ankyrin repeat 1 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). Functional studies have shown that this variant protein exhibits reduced CDK4 and CDK6 binding (PMID: 19260062, 20340136) and partially impaired capacity to inhibit cell proliferation (PMID: 19260062, 23190892, 24659262). This variant has been reported in many individuals affected with melanoma (PMID: 8595405, 9425228, 12072543, 12556369, 17047042, 19260062, 20340136, 22841127, 28830827) and in an individual affected with breast cancer and sarcoma (PMID: 25503501). This variant has also been identified in 3/244916 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Familial melanoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 35 of the CDKN2A (p16INK4a) protein (p.Gly35Ala). This variant is present in population databases (rs746834149, gnomAD 0.003%). This missense change has been observed in individual(s) with melanoma (PMID: 8595405, 9425228, 12072543, 12556369, 19260062, 19759551, 21462282, 22841127; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 98G>C (Gly27Ala). ClinVar contains an entry for this variant (Variation ID: 463481). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 14745721, 19260062, 20340136, 23190892, 24659262). For these reasons, this variant has been classified as Pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2022

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; Observed in individuals with a personal or family history of melanoma (Walker et al., 1995; Soufir et al., 1998; Hearle et al., 2003; Cust et al., 2011; Maxwell et al., 2015); Published functional studies demonstrate reduced ability to bind to CDK4 and CDK6 and altered subcellular localization in some assays, while others showed much higher residual CDK4 binding, intermediate levels of cell proliferation arrest, and no impairment in oxidative or cell cycle function (Kannengiesser et al., 2009; McKenzie et al., 2010; Jenkins et al., 2013; Scaini et al., 2014); This variant is associated with the following publications: (PMID: 26206799, 9425228, 19260062, 24659262, 16905682, 10070944, 9132280, 15146471, 25780468, 18573309, 12556369, 12072543, 28440912, 9823374, 20340136, 23190892, 21462282, 9416844, 25503501, 21325014, 11500805, 8595405, 22841127, 28830827, 17047042, 14745721, 9653180, 9529249, 16173922) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.26

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

D;T;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.75

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.8

D;.;D

REVEL

Pathogenic

0.83

Sift

Benign

0.099

T;.;T

Sift4G

Benign

0.12

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.62

MutPred

0.86

Loss of catalytic residue at G35 (P = 0.0286);Loss of catalytic residue at G35 (P = 0.0286);Loss of catalytic residue at G35 (P = 0.0286);

MVP

0.94

MPC

1.1

ClinPred

0.97

GERP RS

4.9

Varity_R

0.28

gMVP

0.95

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over