rs387906410

chr9-21971019-GC-AG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_000077.5(CDKN2A):c.339_340delinsCT(p.Pro114Ser) 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L113L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 9.18

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-21971019-GC-AG is Pathogenic according to our data. Variant chr9-21971019-GC-AG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9424.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.339_340delinsCT	p.Pro114Ser	missense_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.382_383delinsCT	p.Ala128Leu	missense_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.339_340delinsCT	p.Pro114Ser	missense_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.382_383delinsCT	p.Ala128Leu	missense_variant	2/3	1	NM_058195.4

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2014

This variant is denoted c.339_340delGCinsCT at the cDNA level and p.Pro114Ser (P114S) at the protein level. The normal sequence with the bases that are deleted in braces followed by the inserted bases in brackets is: GTCT{delGC}[insCT]CCGT. The c.339_340delGCinsCT mutation in the CDKN2A gene has been reported previously in associationwith familial cutaneous malignant melanoma (Goldstein et al., 2006; Kannengeisser et al., 2007), and functional studies have shown that the resulting mutatnt protein has significantly reduced binding to CDK4 (Kannengeisser et al., 2009). The insertion and deletion result in the synonymous replacement of the normal Leucine codon (CTG) with a different Leucine codon (CTC) at amino acid position 113, and in the replacement of a Proline codon (CCC) with a Serine codon (TCC) at amino acid position 114. The NHLBI ESP Exome Variant Server reports c.339_340delGCinsCT was not observed in approximately 6,400 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, weinterpret c.339_340delGCinsCT as a disease-causing mutation. The variant is found in CDKN2A panel(s). -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 24, 2022

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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 9053859, 19260062, 23190892, 24659262). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 9424). This variant is also known as c.382_383delinsCT (p.Ala128Leu) in the CDKN2A (p14ARF) transcript. This missense change has been observed in individual(s) with melanoma (PMID: 17492760, 17992122, 21462282). 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 proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 114 of the CDKN2A (p16INK4a) protein (p.Pro114Ser). 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. -

Melanoma, cutaneous malignant, susceptibility to, 2 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 2007

- -

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: rs387906410; hg19: chr9-21971018;