9-21970990-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_000077.5(CDKN2A):c.369T>A(p.His123Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,610,194 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. H123Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 2.98

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 Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in NM_000077.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.014335811).
• BP6: Variant 9-21970990-A-T is Benign according to our data. Variant chr9-21970990-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127526.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=6, Benign=5}.
• BS2: High AC in GnomAd at 195 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.369T>A	p.His123Gln	missense_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.*13T>A		3_prime_UTR_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.369T>A	p.His123Gln	missense_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.*13T>A		3_prime_UTR_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00468

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

GnomAD3 exomes AF: 0.000296 AC: 72 AN: 243602 Hom.: 0 AF XY: 0.000203 AC XY: 27 AN XY: 132824

Gnomad AFR exome AF: 0.00413

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1457860 Hom.: 1 Cov.: 31 AF XY: 0.0000924 AC XY: 67 AN XY: 725448

Gnomad4 AFR exome AF: 0.00442

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74502

Gnomad4 AFR AF: 0.00466

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000448 Hom.: 0

Bravo AF: 0.00132

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000338 AC: 41

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27978560, 25318351, 22885699, 27626068, 18573309, 26601054, 16508961, 26366474, 26342236, 28944238, 26206375, 25186627, 9660926, 9823374, 7882348) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 01, 2022	- -

Melanoma-pancreatic cancer syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 14, 2023	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 19, 2016	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 29, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 04, 2021	Variant summary: CDKN2A c.369T>A (p.His123Gln) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 243602 control chromosomes, predominantly at a frequency of 0.0041 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.369T>A has been reported in the literature in individuals affected with Noonan syndrome/glioneuronal tumors, rectal cancer, and one individual who met health insurance criteria for BRCA1/2 or Lynch syndrome gene testing without a specific phenotype being provided (example, Lin_2016, DeRycke_2017, Yorczyk_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Co-occurrences with other pathogenic variant(s) have been observed at our laboratory and in the literature (our laboratory, BRCA1 c.2679_2682delGAAA, p.Lys893fsX106; Lin_2016, PTPN11 c.923A>G, p.Asn308Ser), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant as evidenced by similar cell proliferation and viability levels as wild-type CDKN2A (Kwong-Shing Ng_2018). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus leaning towards a likely benign/benign outcome. Based on the evidence outlined above, the variant was classified as benign. -

Familial melanoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Benign	17
Dann	Benign	0.94
DEOGEN2	Uncertain	0.54	D;T;.;.;.;.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	T;T;.;T;.;T;T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	0.70	D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.1	D;.;.;D;.;.;.;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.46
MutPred		0.64		Gain of MoRF binding (P = 0.1031);Gain of MoRF binding (P = 0.1031);.;Gain of MoRF binding (P = 0.1031);.;.;.;.;
MVP		0.99
MPC		1.1
ClinPred		0.23	T
GERP RS		3.0
Varity_R		0.47
gMVP		0.57

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: rs6413463; hg19: chr9-21970989; COSMIC: COSV58721567; COSMIC: COSV58721567;