rs1034265990

Variant names:

• chr9-21971123-G-A
• rs1034265990
• NM_000077.5:c.236C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-21971123-G-A
• chr9-21971123-G-C
• chr9-21971123-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BS2_Supporting

The NM_000077.5(CDKN2A):​c.236C>T​(p.Thr79Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,451,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T79S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.75
• Publications: 14 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 45 uncertain in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.236C>T	p.Thr79Ile	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.279C>T	p.His93His	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.236C>T	p.Thr79Ile	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.279C>T	p.His93His	synonymous_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000436 AC: 1 AN: 229620 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000568

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1451540 Hom.: 0 Cov.: 31 AF XY: 0.00000415 AC XY: 3 AN XY: 722510

African (AFR) AF: 0.00 AC: 0 AN: 33444

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5488

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111500

Other (OTH) AF: 0.00 AC: 0 AN: 60238

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Apr 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T79I variant (also known as c.236C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 236. The threonine at codon 79 is replaced by isoleucine, an amino acid with similar properties. Of note, this alteration is also known as c.279C>T (p.H93H)in the p14(ARF) isoform. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Feb 03, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

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 threonine with isoleucine at codon 79 of the CDKN2A (p16INK4A) protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with paraganglioma (PMID: 33397043). This variant has been identified in 1/229620 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Feb 05, 2024

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.236C>T (p.Thr79Ile) results in a non-conservative amino acid change in 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 4.4e-06 in 229620 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.236C>T has been reported in the literature in individuals affected with paraganglioma or biliary tract cancer as well as unaffected controls (Seo_2020, Okawa_2023). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33397043, 36243179). ClinVar contains an entry for this variant (Variation ID: 630548). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Feb 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial melanoma Uncertain:1

May 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 79 of the CDKN2A (p16INK4a) protein (p.Thr79Ile). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 630548). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	0.81
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;.;.;.;.;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
PhyloP100		1.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.5	D;.;.;D;.;.;.;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0050	D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.037	D;D;D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.;.;.
Vest4		0.16
MutPred		0.47		Gain of catalytic residue at P81 (P = 0.0305);Gain of catalytic residue at P81 (P = 0.0305);.;Gain of catalytic residue at P81 (P = 0.0305);.;.;.;.;
MVP		1.0
MPC		1.1
ClinPred		0.88	D
GERP RS		5.0
PromoterAI		-0.0030	Neutral
Varity_R		0.32
gMVP		0.77
Mutation Taster		=10/90	disease causing

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: rs1034265990; hg19: chr9-21971122; COSMIC: COSV58683990;