chr9-21971028-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BS2_Supporting

The NM_000077.5(CDKN2A):c.331G>A(p.Gly111Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,454,378 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G111V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 2.87

Publications

13 publications found

Variant links:

COSMIC-nc: COSV58718063

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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 46 uncertain in NM_000077.5

BS2

High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000077.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDKN2A	NM_000077.5	MANE Select	c.331G>A	p.Gly111Ser	missense	Exon 2 of 3	NP_000068.1
CDKN2A	NM_058195.4	MANE Plus Clinical	c.374G>A	p.Gly125Glu	missense	Exon 2 of 3	NP_478102.2
CDKN2A	NM_001195132.2		c.331G>A	p.Gly111Ser	missense	Exon 2 of 4	NP_001182061.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.331G>A	p.Gly111Ser	missense	Exon 2 of 3	ENSP00000307101.5
CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.374G>A	p.Gly125Glu	missense	Exon 2 of 3	ENSP00000462950.1
CDKN2A	ENST00000498124.1	TSL:1	c.331G>A	p.Gly111Ser	missense	Exon 2 of 4	ENSP00000418915.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000421

AC:

AN:

237514

AF XY:

0.00

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:

0.00000929

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1454378

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5194

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111482

Other (OTH)

AF:

0.00

AC:

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

Cov.:

ExAC

AF:

0.00000832

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Melanoma-pancreatic cancer syndrome

Uncertain:2

Apr 20, 2023

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

Aug 22, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Hereditary cancer-predisposing syndrome

Uncertain:2

Apr 15, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G111S variant (also known as c.331G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 331. The glycine at codon 111 is replaced by serine, an amino acid with similar properties. This alteration has been reported in two population-based studies of individuals affected with melanoma, but was not reported in 1084 controls (Harland M et al. Hered Cancer Clin Pract. 2014 Nov;12:20; Cust AE et al. J. Med. Genet. 2011 Apr;48:266-72). A functional study reported this variant as neutral based on in vitro assessment of the impact on proliferation in human pancreatic cancer cell lines (Kimura H et al. Elife. 2022 01;11:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Of note, this alteration is also known as c.374G>A (p.Gly125Glu) in the p14(ARF) isoform. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Feb 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces glycine with serine at codon 111 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function. In a functional study, this variant did not impact cell cycle progression (PMID: 35001868). This variant has been reported in an individual affected with melanoma (PMID: 21325014). This variant has been identified in 1/237514 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.

Familial melanoma

Uncertain:1

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 111 of the CDKN2A (p16INK4a) protein (p.Gly111Ser). This variant is present in population databases (rs778971134, gnomAD 0.0009%). This missense change has been observed in individual(s) with melanoma (PMID: 21325014). This variant is also known as c.374G>A (p.Gly125Glu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 463499). 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 does not substantially affect 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.097

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.43

MetaRNN

Uncertain

0.44

MetaSVM

Pathogenic

0.99

PhyloP100

2.9

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.36

MVP

1.0

ClinPred

0.95

GERP RS

5.9

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.46

Mutation Taster

=0/100

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over