9-21974793-G-T

Position:

• chr9-21974793-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.35C>A​(p.Ser12Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S12S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.0700

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 163 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21974793-G-T is Pathogenic according to our data. Variant chr9-21974793-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 630390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.35C>A	p.Ser12Ter	stop_gained	1/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.194-3585C>A		intron_variant		ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.35C>A	p.Ser12Ter	stop_gained	1/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.194-3585C>A		intron_variant		1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 09, 2021	The p.S12* pathogenic mutation (also known as c.35C>A), located in coding exon 1 of the CDKN2A gene, results from a C to A substitution at nucleotide position 35. This changes the amino acid from a serine to a stop codon within coding exon 1. This alteration has been reported in patients affected with melanoma (Casula M et al. J Clin Oncol, 2004 Jan;22:286-92; Seifert BA et al. Clin Cancer Res, 2016 Aug;22:4087-4094; Taylor NJ et al. J Invest Dermatol, 2017 12;137:2606-2612). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 05, 2018	- -

Familial melanoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 03, 2023	ClinVar contains an entry for this variant (Variation ID: 630390). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 17055252, 27083775, 28830827). This sequence change creates a premature translational stop signal (p.Ser12*) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 12, 2021	Variant summary: CDKN2A c.35C>A (p.Ser12X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 234484 control chromosomes (gnomAD and publication data). c.35C>A has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Casula_2004, Seifert_2016, Taylor_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

CDKN2A-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 03, 2023

The CDKN2A c.35C>A variant is predicted to result in premature protein termination (p.Ser12*). This variant corresponds to c.35C>A (p.Ser*) in both p16INK4A (NM_000077.4) and p14ARF (NM_058195.3). This variant has been reported in individuals with cutaneous malignant melanoma (Table 1, Casula et al. 2007. PubMed ID: 17055252; Table 1, Casula et al. 2009. PubMed ID: 19799798; Table S3, Taylor et al. 2017. PubMed ID: 28830827). It has also been reported in an individual with a personal history of breast cancer and multiple melanomas (Table 2, Seifert et al. 2016. PubMed ID: 27083775). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/630390/). Nonsense variants in CDKN2A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.20	N
MutationTaster	Benign	1.0	A;A;A;A;N;N;N;N;N
Vest4		0.56
GERP RS		0.77

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

Other links and lift over

dbSNP: rs141798398; hg19: chr9-21974792; COSMIC: COSV58689693; COSMIC: COSV58689693;