rs876658534

Positions:

• chr9-21971156-GC-AA

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_Moderate PM1 PM2 PM5 PP3 PP5_Very_Strong

The ENST00000304494.10(CDKN2A):​c.202_203delinsTT​(p.Ala68Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. 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 ENST00000304494.10 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.23

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PS1: Transcript ENST00000304494.10 (CDKN2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in ENST00000304494.10
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 1000204.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• 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 id is 230375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.202_203delinsTT	p.Ala68Leu	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.245_246delinsTT	p.Arg82Leu	missense_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.202_203delinsTT	p.Ala68Leu	missense_variant	2/3	1	NM_000077.5	ENSP00000307101	P2
CDKN2A	ENST00000579755.2	c.245_246delinsTT	p.Arg82Leu	missense_variant	2/3	1	NM_058195.4	ENSP00000462950

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Mar 08, 2023

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2024

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. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial melanoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 17, 2023

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. 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. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 11518711, 19260062, 20340136, 21462282). 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. ClinVar contains an entry for this variant (Variation ID: 230375). This variant is also known as c.245_246delinsTT (p.Arg82Leu) in the CDKN2A (p14ARF) transcript. This missense change has been observed in individual(s) with cutaneous melanoma and/or renal cancer (PMID: 9425228, 18983535, 25780468, 30274933, 30291219, 32782288). It has also been observed to segregate with disease in related individuals. 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 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). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876658534; hg19: chr9-21971155;