rs876658534

Variant names:

• chr9-21971156-GC-AA
• rs876658534
• NM_000077.5:c.202_203delGCinsTT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM5 PP3 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.202_203delGCinsTT​(p.Ala68Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A68P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.23
• Publications: 11 publications found

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

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 42 uncertain in NM_000077.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-21971157-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1000204.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-21971156-GC-AA is Pathogenic according to our data. Variant chr9-21971156-GC-AA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 230375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.202_203delGCinsTT	p.Ala68Leu	missense_variant		ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.245_246delGCinsTT	p.Arg82Leu	missense_variant		ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.202_203delGCinsTT	p.Ala68Leu	missense_variant		1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.245_246delGCinsTT	p.Arg82Leu	missense_variant		1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma-pancreatic cancer syndrome Pathogenic:1

Mar 08, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 20340136, 11518711]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9425228, 26775776, 25780468]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 11, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.202_203delGCinsTT variant (also known as p.A68L) is located in coding exon 2 of the CDKN2A gene and results from an in-frame deletion of GC and insertion of TT between nucleotide positions 202 and 203. The alanine at codon 68 is replaced by leucine. This variant has been previously reported in several kindreds with malignant melanoma (Pastorino L et al, Pigment Cell Melanoma Res 2008 Dec; 21(6):700-9; Cust AE et al, J. Med. Genet. 2011 Apr; 48(4):266-72; Maubec E et al. J Am Acad Dermatol 2012 Dec;67(6):1257-64; Bruno W et al. J Am Acad Dermatol 2016 Feb;74(2):325-32; De Simone P et al. Int J Mol Sci, 2020 Dec;21). In one family, the alteration was found to segregate with disease in four individuals (Soufir N et al, Hum. Mol. Genet. 1998 Feb; 7(2):209-16). This variant was also detected in 1/422 Italian pancreatic cancer patients (Puccini A et al. Cancers (Basel), 2022 Sep;14). In addition, functional studies of A68L mutants have demonstrated decreased binding affinity to CDK4, irregular nuclear localization, and reduced mediation of cell-cycle arrest compared to wild type (Rizos H et al, J. Biol. Chem. 2001 Nov; 276(44):41424-34; McKenzie HA et al. Hum Mutat 2010 Jun;31(6):692-701; Miller PJ et al, Hum. Mutat. 2011 Aug; 32(8):900-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial melanoma Pathogenic:1

Mar 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

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 alanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 68 of the CDKN2A (p16INK4a) protein (p.Ala68Leu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with cutaneous melanoma, pancreatic cancer and/or renal cancer (PMID: 9425228, 18983535, 25780468, 30274933, 30291219, 32782288, 36139606). It has also been observed to segregate with disease in related individuals. This variant is also known as c.245_246delinsTT (p.Arg82Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 230375). 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: 11518711, 19260062, 20340136, 21462282). This variant disrupts the p.Ala68 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been observed in individuals with CDKN2A (p16INK4a)-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic. In the absence of additional clinical evidence, this variant has been classified as Likely Pathogenic. While this evidence indicates that the variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, the association of this variant with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=0/100	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876658534; hg19: chr9-21971155;