rs864622263

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-21974781-A-C
• chr9-21974781-A-G
• chr9-21974781-A-T

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>G​(p.Leu16Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L16P) 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: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 9-21974781-A-C is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.47T>G	p.Leu16Arg	missense_variant	Exon 1 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3573T>G		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>G	p.Leu16Arg	missense_variant	Exon 1 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194-3573T>G		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455866 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 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: 9.00e-7 AC: 1 AN: 1111262

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.000881 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Oct 29, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A c.47T>G (p.Leu16Arg) variant has been reported in the published literature in individuals and families affected with melanoma and/or pancreatic cancer (PMIDs: 33823155 (2021), 33766116 (2021), 32482799 (2021)). Additionally, functional evidence suggests that this variant may impact protein function (PMID: 33823155 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: impaired cell cycle control and abolished interaction with CDK4 and CDK6 (PMID: 33823155); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30039340, 12072543, 9425228, 21150883, 21462282, 17047042, 16234564, 20340136, 15173226, 16896043, 20876876, 10861313, 16905682, 16172233, 25356972, 17218939, 28726808, 29922827, 28830827, 29661971, 34399810, 32482799, 33823155) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 10, 2022

Color Diagnostics, LLC DBA Color Health

Significance: 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 missense variant replaces leucine with arginine at codon 16 of the CDKN2A (p16INK4A) protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant results in reduced protein expression levels, inability to bind CDK4/CDK6, and impairment of the cell cycle control activity (PMID: 33823155). This variant has been reported in individuals and families affected with melanoma (PMID: 10861313, 12072543, 15146471, 15173226, 16169933, 16172233, 16234564, 16896043, 17218939, 21150883, 21462282, 25685612) and pancreatic cancer (PMID: 25356972). This variant has been observed in four multi-generational families affected with malignant melanoma and pancreatic cancer, where this variant has shown segregation with cancers in an autosomal dominant manner (PMID: 33823155). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at this position, p.Leu16Pro, has been shown to impair p16INK4A protein function and is classified as Pathogenic (PMID: 20340136; ClinVar variation ID: 649266), indicating that leucine at this position is important for p16INK4A protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Aug 19, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L16R pathogenic mutation (also known as c.47T>G), located in coding exon 1 of the CDKN2A gene, results from a T to G substitution at nucleotide position 47. The leucine at codon 16 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been observed in multiple individuals with personal and/or family history of melanoma and/or pancreatic cancer (Goldstein AM et al. J. Natl. Cancer Inst. 2000 Jun; 92(12):1006-10; Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11; Horn IP et al. J Biol Chem 2021 Apr;296:100634; Overbeek KA et al. J Med Genet, 2021 04;58:264-269; Ambry internal data) and has been shown to segregate with disease in several melanoma families (Goldstein AM et al. J. Natl. Cancer Inst. 2000 Jun; 92(12):1006-10; Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11). Another pathogenic alteration impacting the same codon, p.L16P, has also been observed to segregate with melanoma in several families (Soufir N et al. Hum. Mol. Genet. 1998 Feb; 7(2):209-16; Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11) and has been associated with protein mislocalization and reduced binding to CDK4 and CDK6 (McKenzie HA et al. Hum. Mutat. 2010 Jun; 31(6):692-701). This amino acid position is well 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial melanoma Pathogenic:1

Nov 09, 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 arginine, which is basic and polar, at codon 16 of the CDKN2A (p16INK4a) protein (p.Leu16Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and pancreatic cancer (PMID: 15173226, 16169933, 17218939, 21150883; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 219815). 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. 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: 17624602, 20340136, 21462282). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;T;.
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.32	D
PhyloP100		5.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.8	D;.;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.025	D;.;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.56		Gain of methylation at L16 (P = 0.0266);Gain of methylation at L16 (P = 0.0266);Gain of methylation at L16 (P = 0.0266);
MVP		0.98
MPC		1.5
ClinPred		0.99	D
GERP RS		3.7
PromoterAI		0.0012	Neutral
Varity_R		0.77
gMVP		1.0
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: rs864622263; hg19: chr9-21974780; COSMIC: COSV58729402; COSMIC: COSV58729402;