rs121913386

chr9-21971018-G-Achr9-21971018-G-Cchr9-21971018-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000077.5(CDKN2A):c.341C>T(p.Pro114Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. P114H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 9.18

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 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 chr9-21971018-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2449062.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 9-21971018-G-A is Pathogenic according to our data. Variant chr9-21971018-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 77637.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.341C>T	p.Pro114Leu	missense_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.384C>T	p.Ala128=	synonymous_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.341C>T	p.Pro114Leu	missense_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.384C>T	p.Ala128=	synonymous_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial melanoma Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 11, 2020	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. This variant has been reported to affect CDKN2A (p16INK4a) protein function (PMID: 7777060, 7777061, 8668202, 9328469, 9053859, 12606942, 21462282). This variant has been observed in several individuals affected with melanoma (PMID: 9856841, 21462282). Segregation studies have not been reported. ClinVar contains an entry for this variant (Variation ID: 77637). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 114 of the CDKN2A (p16INK4a) protein (p.Pro114Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2021	Variant summary: CDKN2A c.341C>T (p.Pro114Leu) 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 239394 control chromosomes (gnomAD). c.341C>T has been reported as a germline mutation in the literature in several individuals affected with familial melanoma (e.g. Fargnoli_1998, Spica_2011, Pellegrini_2019). However, no co-segregation studies have been performed, therefore these data do not allow any definitive conclusion about variant significance. The variant has also been reported numerous times as a somatic mutation in melanomas and other cancers. Multiple publications report experimental evidence evaluating an impact on protein function, indicating that the variant is non-functional and unable to bind Cdk4/Cdk6 or induce G1 cell cycle arrest in-vitro (e.g. Koh_1995, Parry_1996, Byeon_1998, Jiang_1998, Gump_2001, Miller _2011). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as pathogenic and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Squamous cell carcinoma of the skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant tumor of urinary bladder Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Urology, Hospital Clinic de Barcelona

-

- -

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2020

The p.P114L variant (also known as c.341C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 341. The proline at codon 114 is replaced by leucine, an amino acid with similar properties. This alteration is non functional in multiple studies including with respect to CDK4/6 binding and cell cycle control (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; Parry and Peters, Mol. Cell. Biol. 1996 Jul;16(7):3844-52; Tevelev A et al. Biochemistry 1996 Jul;35(29):9475-87). This alteration has been observed in multiple individuals who have a personal or family history that is consistent with CDKN2A-associated disease (Ambry internal data; Fargnoli MC et al. J. Invest. Dermatol., 1998 Dec;111:1202-6; 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 the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;T;.;.;.;.;T;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-9.4	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.94
MutPred		0.89		Gain of MoRF binding (P = 0.061);Gain of MoRF binding (P = 0.061);.;Gain of MoRF binding (P = 0.061);.;.;.;.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.82
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121913386; hg19: chr9-21971017; COSMIC: COSV58683051; COSMIC: COSV58683051;