rs1060501260

Variant names:

• chr9-21971156-G-A
• rs1060501260
• NM_000077.5:c.203C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-21971156-G-A
• chr9-21971156-G-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000077.5(CDKN2A):​c.203C>T​(p.Ala68Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3 O:1
• Conservation: PhyloP100: 9.23
• Publications: 22 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 11 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
• 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 VariationId is 1000204.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 9-21971156-G-A is Pathogenic according to our data. Variant chr9-21971156-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406701.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.203C>T	p.Ala68Val	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.246C>T	p.Arg82Arg	synonymous_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.203C>T	p.Ala68Val	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.246C>T	p.Arg82Arg	synonymous_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441598 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717166

African (AFR) AF: 0.00 AC: 0 AN: 33234

American (AMR) AF: 0.00 AC: 0 AN: 44010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39256

South Asian (SAS) AF: 0.00 AC: 0 AN: 85480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5264

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108912

Other (OTH) AF: 0.00 AC: 0 AN: 59842

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Melanoma-pancreatic cancer syndrome Pathogenic:2

Feb 14, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35001868]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 32482799, 11075991, 21462282, Myriad internal data]. -

Jun 13, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Sep 23, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A68V variant (also known as c.203C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 203. The alanine at codon 68 is replaced by valine, an amino acid with similar properties. This alteration has been detected in several melanoma-affected kindreds as well as an individual affected with pancreatic cancer (among other cancers); although it did not completely segregate with disease (FitzGerald MG et al. Proc. Natl. Acad. Sci. U.S.A., 1996 Aug;93:8541-5; Gerdes B et al. Pancreas, 2000 Nov;21:369-75; Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11; Potjer TP et al. J. Med. Genet., 2018 10;55:661-668; Ambry internal data). A functional study reported this variant as deleterious based on in-vitro assessment of impact on proliferation in human pancreatic cancer cell lines (Kimura H et al. Elife, 2022 Jan;11:). Internal analysis shows that this amino acid position lies within a structural hotspot where many pathogenic mutations are found and it is likely to affect binding to CDK4 (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Mar 04, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma and neural system tumor syndrome Uncertain:1

Feb 14, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial melanoma Uncertain:1

Jan 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 68 of the CDKN2A (p16INK4a) protein (p.Ala68Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma, pancreatic cancer, vocal cord cancer, and basal cell carcinoma (PMID: 8710906, 11075991, 21462282, 32482799). ClinVar contains an entry for this variant (Variation ID: 406701). 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: 35001868). This variant disrupts the p.Ala68 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425228, 11518711, 18983535, 19260062, 20340136, 21462282, 25780468). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Melanoma and neural system tumor syndrome;C1838547:Melanoma-pancreatic cancer syndrome Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 07-16-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;T;.;.;.;.;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
PhyloP100		9.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.74
MutPred		0.86		Gain of catalytic residue at A68 (P = 0.0776);Gain of catalytic residue at A68 (P = 0.0776);.;Gain of catalytic residue at A68 (P = 0.0776);.;.;.;.;
MVP		0.99
MPC		1.2
ClinPred		0.98	D
GERP RS		5.8
PromoterAI		0.015	Neutral
Varity_R		0.54
gMVP		0.85
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1060501260; hg19: chr9-21971155; COSMIC: COSV58689853; COSMIC: COSV58689853;