NM_000077.5:c.249C>A

Variant names:

• chr9-21971110-G-T
• rs34968276
• NM_000077.5:c.249C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000077.5(CDKN2A):​c.249C>A​(p.His83Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,452,116 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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 6.18

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]

ENSG00000264545 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 42 pathogenic changes around while only 12 benign (78%) in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 9-21971110-G-T is Pathogenic according to our data. Variant chr9-21971110-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429110.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.249C>A	p.His83Gln	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.292C>A	p.Arg98Arg	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.249C>A	p.His83Gln	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.292C>A	p.Arg98Arg	synonymous_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452116 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722770

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 12, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H83Q pathogenic mutation (also known as c.249C>A), located in coding exon 2 of the CDKN2A gene, results from a C to A substitution at nucleotide position 249. The histidine at codon 83 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with melanoma as well as an Italian familial melanoma kindred (Begg CB et al. J Natl Cancer Inst. 2005 Oct 19;97(20):1507-15; Berwick M et al. Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1520-5; Orlow I et al. J Invest Dermatol. 2007 May;127(5):1234-43; Pedace L et al. Cancer Epidemiol. 2011 Dec;35(6):e116-20). Additionally, two disease-causing mutations, p.H83Y and p.H83N, have been described in the same codon (Yarbrough WG et al. J Natl Cancer Inst. 1999 Sep 15;91(18):1569-74; Lang J et al. Br J Dermatol. 2005 Dec;153(6):1121-5). This alteration has been observed in individuals who have a personal or family history that is consistent with CDKN2A-associated disease (Ambry internal data). Based on internal structural assessment, this alteration disrupts the ankyrin domain near its interface with kinases (Ambry internal data; Russo AA et al. Nature.1998 Sep;395(6699):237-43). 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 the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not specified Uncertain:1

Mar 07, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDKN2A c.249C>A (p.His83Gln) results in a non-conservative amino acid change located in the Ankyrin repeat containing domain (IPR020683) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 231524 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.249C>A has been reported in the literature in at-least one patient with Single primary melanoma with authorship/patient overlap among subsequent studies (example, Begg_2005, Berwick_2006, Orlow_2007), in at-least one patient in the melanoma genetics consortium cohort (Demenais_2010), a patient with sporadic melanoma with no reported family history (Miller_2011), in the setting of familial melanoma originating from Italy with no reported co-segregation evidence and possible cohort overlap (example, Pedace_2011, Pellegrini_2017, De Simone_2020). These report(s) do not provide unequivocal conclusions about association of the variant with inherited Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial melanoma Uncertain:1

Dec 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 83 of the CDKN2A (p16INK4a) protein (p.His83Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with sporadic or familial melanoma (PMID: 16234564, 16307646, 16896043, 17218939, 20876876, 21462282, 21507037, 21893440, 28146043, 32221274). This variant is also known as c.247C>A, c.295C>A. ClinVar contains an entry for this variant (Variation ID: 429110). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;T;.;.;.;.;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.019	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.5	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.63		Loss of catalytic residue at D84 (P = 0.0533);Loss of catalytic residue at D84 (P = 0.0533);.;Loss of catalytic residue at D84 (P = 0.0533);.;.;.;.;
MVP		0.95
MPC		1.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.78
gMVP		0.85

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: rs34968276; hg19: chr9-21971109; COSMIC: COSV58684711; COSMIC: COSV58684711;