rs1060501266

Variant names:

• chr9-21968347-T-C
• rs1060501266
• NM_000077.5:c.458-105A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PP3_Moderate PP5_Very_Strong BS2

The NM_000077.5(CDKN2A):​c.458-105A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,525,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CDKN2A NM_000077.5 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: -3.10
• Publications: 8 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: Likely_pathogenic. The variant received 6 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-21968347-T-C is Pathogenic according to our data. Variant chr9-21968347-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 406715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.458-105A>G		intron_variant	Intron 2 of 2	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.*102-105A>G		intron_variant	Intron 2 of 2	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.458-105A>G		intron_variant	Intron 2 of 2	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.*102-105A>G		intron_variant	Intron 2 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 16 AN: 1373396 Hom.: 0 AF XY: 0.0000117 AC XY: 8 AN XY: 684098

African (AFR) AF: 0.00 AC: 0 AN: 31742

American (AMR) AF: 0.00 AC: 0 AN: 39888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25272

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38612

South Asian (SAS) AF: 0.00 AC: 0 AN: 81792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4412

European-Non Finnish (NFE) AF: 0.0000144 AC: 15 AN: 1042450

Other (OTH) AF: 0.00 AC: 0 AN: 57362

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in aberrant splicing in a gene for which loss of function is a known mechanism of disease (Harland et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25685612, 16905682, 25780468, 26542317, 18612309, 22841127, 21614589, 21325014, 25023876, 11726555, 29215650, 23348723, 33322357, 15009729)

Jun 16, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:2

Oct 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.458-105A>G intronic variant results from an A to G substitution 105 nucleotides upstream from coding exon 3 in the CDKN2A gene. This alteration has been reported in multiple melanoma families and was shown to segregate with disease, although there were unaffected carriers in these families (ages unknown) (Harland M et al. Hum Mol Genet. 2001 Nov;10:2679-86; Goldstein AM et al. Genes Chromosomes Cancer. 2005 Jun;43(2):128-36; Maubec E et al. J Am Acad Dermatol 2012 Dec;67(6):1257-64; Puig S et al. Genet Med. 2016 Jul;18(7):727-36). This alteration was confirmed to be a de novo alteration in an individual with eight cutaneous melanomas (Majore S et al. J Invest Dermatol. 2004 Feb;122(2):450-1). This alteration was shown to generate two alternate transcripts that retain all or part of intron 2 which encodes a stop codon. Although it was not empirically shown, if these transcripts escape nonsense-mediated mRNA decay, the authors predict that protein product is likely to be structurally and functionally similar to the wildtype protein as they will only differ by four C-terminal amino acids (Harland M et al. Hum Mol Genet. 2001 Nov;10:2679-86). Of note, this variant is also designated as "IVS2-105A>G" in published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as a disease-causing mutation.

Dec 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant causes an A to G nucleotide substitution at the -105 position of intron 2 of the CDKN2A (p16INK4A) gene. This variant is also known as IVS2-105A>G in the literature. A non-quantitative RNA study has shown that this variant disrupts RNA splicing and causes aberrant retention of the entire, or almost all of, intron 2 sequence, resulting in the mutant transcripts that are much longer than the normal transcript (PMID: 11726555). This variant has been reported in over twenty individuals affected with familial cutaneous melanoma (PMID: 11726555, 15009729, 16905682, 22841127) and has been shown to segregate with disease in two families (PMID: 11726555). In addition, this variant has been observed to be de novo in an individual affected with multiple primary melanomas (PMID: 15009729). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

Sep 01, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2001

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Melanoma and neural system tumor syndrome Pathogenic:1

Mar 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Melanoma-pancreatic cancer syndrome Pathogenic:1

Nov 25, 2024

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: 11726555]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11726555, 15009729, 21614589, 22841127, Myriad internal data].

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial melanoma Pathogenic:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 2 of the CDKN2A (p16INK4a) gene. It does not directly change the encoded amino acid sequence of the CDKN2A (p16INK4a) protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cutaneous melanoma (PMID: 11726555, 15009729, 16905682, 22841127). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2-105A>G. ClinVar contains an entry for this variant (Variation ID: 406715). Studies have shown that this variant results in inclusion of most or all of intron 2 in the CDKN2A (p16INK4a) mRNA and introduces a new termination codon (PMID: 11726555). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.12
DANN	Benign	0.58
PhyloP100		-3.1
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 1

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

Other links and lift over

dbSNP: rs1060501266; hg19: chr9-21968346;