9-21974781-A-G

Variant names:

• chr9-21974781-A-G
• rs864622263
• NM_000077.5:c.47T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.47T>C​(p.Leu16Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,866 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L16R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.50
• Publications: 24 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 16 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 52 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 chr9-21974781-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 219815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 9-21974781-A-G is Pathogenic according to our data. Variant chr9-21974781-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 649266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.47T>C	p.Leu16Pro	missense_variant	Exon 1 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3573T>C		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.47T>C	p.Leu16Pro	missense_variant	Exon 1 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194-3573T>C		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455866 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724558

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111262

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial melanoma Pathogenic:2

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 16 of the CDKN2A (p16INK4a) protein (p.Leu16Pro). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu16 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15173226, 16169933, 17218939, 21150883; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 8573142, 10498896, 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: 649266). This missense change has been observed in individual(s) with melanoma (PMID: 9425228, 11500805, 16905682, 17624602, 19759551, 21462282). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Feb 22, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDKN2A c.47T>C (p.Leu16Pro) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 232396 control chromosomes (gnomAD). c.47T>C has been reported in the literature in individuals affected with cutaneous melanoma as well as other associated cancers (Jovanovic_2010, Monnerat_2007, Soufir_1998). These data indicate that the variant is likely to be associated with disease. One study involving segregation analysis in a family, identified the variant in 3 affected family members and 2 unaffected without however specifying the age of the unaffected individuals; these data suggest a reduced penetrance for the variant of interest, in accordance with an overall reduced penetrance expected for CDKN2A variants. Experimental evidence demonstrated the variant to result in loss of function to the CDKN2A protein as shown by impaired CDK4 and CDK6 binding activity, increased Ki67 index in cell culture and altered subcellular distribution (Miller_2011, McKenzie_2010). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 13, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L16P variant (also known as c.47T>C), located in coding exon 1 of the CDKN2A gene, results from a T to C substitution at nucleotide position 47. The leucine at codon 16 is replaced by proline, an amino acid with similar properties. This alteration has been identified in multiple individuals with cutaneous melanoma (Soufir N et al. Hum Mol Genet, 1998 Feb;7:209-16; Monnerat C et al. Fam Cancer, 2007 Jul;6:453-61; Maubec E et al. J Am Acad Dermatol, 2012 Dec;67:1257-64; Aoude LG et al. Twin Res Hum Genet, 2015 Apr;18:126-33). This alteration also demonstrated severely reduced CDK4 and CDK6 binding in functional assays (Ruas M et al. Oncogene, 1999 Sep;18:5423-34; McKenzie HA et al. Hum Mutat, 2010 Jun;31:692-701; Miller PJ et al. Hum Mutat, 2011 Aug;32:900-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on internal structural analysis, L16P results in destabilization of CDKN2A (Russo AA et al. Nature, 1998 Sep;395:237-43). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;T;.
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.32	D
PhyloP100		5.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.5	D;.;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.58		Loss of stability (P = 0.0305);Loss of stability (P = 0.0305);Loss of stability (P = 0.0305);
MVP		0.98
MPC		1.6
ClinPred		0.98	D
GERP RS		3.7
PromoterAI		0.052	Neutral
Varity_R		0.92
gMVP		1.0
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs864622263; hg19: chr9-21974780; COSMIC: COSV58693684; COSMIC: COSV58693684;