9-21974679-T-C

Position:

chr9-21974679-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000077.5(CDKN2A):c.149A>G(p.Gln50Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q50H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense, splice_region

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 4.65

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 1 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 chr9-21974679-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.866

PP5

Variant 9-21974679-T-C is Pathogenic according to our data. Variant chr9-21974679-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 232304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.149A>G	p.Gln50Arg	missense_variant, splice_region_variant	1/3	ENST00000304494.10
CDKN2A	NM_058195.4 linkuse as main transcript	c.194-3471A>G		intron_variant		ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.149A>G	p.Gln50Arg	missense_variant, splice_region_variant	1/3	1	NM_000077.5	P2	P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.194-3471A>G		intron_variant		1	NM_058195.4		Q8N726-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249628

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135142

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 21, 2021	The p.Q50R pathogenic mutation (also known as c.149A>G), located in coding exon 1 of the CDKN2A gene, results from an A to G substitution at nucleotide position 149. The glutamine at codon 50 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in numerous melanoma and pancreatic cancer cohorts (Walker GJ et al. Hum. Mol. Genet. 1995 Oct;4:1845-52; Box NF et al. Am. J. Hum. Genet. 2001 Oct;69:765-73; Pollock PM et al. Genes Chromosomes Cancer. 2001 Sep;32:89-94; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77; Bruno W et al. Oncotarget. 2018 Jun;9:28798; Ambry internal data). It was also found to segregate with melanoma in at least six melanoma-affected individuals in one family (Walker GJ et al. Hum. Mol. Genet. 1995 Oct;4:1845-52; Box NF et al. Am. J. Hum. Genet. 2001 Oct;69:765-73). Based on internal structural analysis, this amino acid substitution is anticipated to result in a significant decrease in structural stability (Russo AA et al. Nature. 1998 Sep;395:237-43; Ambry internal data). A different substitution at the same position (CDKN2A c.149A>C, p.Q50P) shows both a splice defect and defective CDK4 binding by the native protein harboring only the missense change (Loo JC et al. Oncogene. 2003 Sep; 22(41):6387-94). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 21, 2023	This missense variant replaces glutamine with arginine at codon 50 in the ankyrin repeat 2 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). Functional studies showed that this variant affected cell cycle control and failed to suppress cell proliferation (PMID: 35001868). Splice site prediction tools suggest that this variant may impact RNA splicing, although this prediction has not been investigated in RNA studies. This variant has been reported in individuals and families affected with melanoma (PMID: 11477665, 12072543, 16905682, 26681309, 26775776, 28830827, 29464027, 32455486; Cardelli 2020, dissertation, University of L'Aquila; Haghighat, et al. P-07, CGA-IGC 2022) and familial pancreatic cancer (PMID 25356972). This variant has been shown to segregate with disease in six related individuals affected with melanoma (PMID: 8595405). This variant has been identified in 1/249628 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Notably, a different nucleotide substitution at the same position, c.149A>C (p.Gln50Pro), has been observed in individuals affected with melanoma (Clinvar Variation ID: 187713) and shown to affect RNA splicing and p16INK4A protein function (PMID: 14508519). Based on the available evidence, this variant is classified as Pathogenic. -

Familial melanoma

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 50 of the CDKN2A (p16INK4a) protein (p.Gln50Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 8595405, 11477665, 11500805, 25356972, 26775776). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 232304). 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. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 8573142, 35001868). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 31, 2020	Variant summary: CDKN2A c.149A>G (p.Gln50Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249628 control chromosomes. c.149A>G has been reported in the literature in individuals affected with melanoma (Walker_1995, Pollock_2001, Puig_2016, Bruno_2016) and familial pancreatic cancer (Zhen_2015). In one family, 6 transmissions of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Walker_1995). These data indicate that the variant is likely to be associated with disease. Co-occurrence with a pathogenic variant has been reported (CHEK2 c.1283C>T, p.Ser428Phe), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Melanoma and neural system tumor syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 29, 2024

- -

Squamous cell carcinoma of the skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Pancreatic adenocarcinoma

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

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2022

Published functional studies demonstrate a damaging effect: improper protein refolding and impaired ability to regulate cellular proliferation (Tang 1999, Kimura 2022); Observed in individuals with melanoma or pancreatic cancer and segregated with disease in at least one family (Walker 1995, Pollock 2001, Bishop 2002, Goldstein 2004, Goldstein 2007, Zhen 2015, Bruno 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21462282, 9461066, 18573309, 11500805, 23178718, 11477665, 15146471, 25356972, 12072543, 16905682, 10596908, 11687599, 9917418, 8595405, 9653180, 9529249, 16173922, 28830827, 26775776, 9751050, 9823374, 26619011, 26681309, 35001868) -

Melanoma-pancreatic cancer syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 09, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35001868]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8595405, 11477665, 26775776, 25356972]. -

Malignant melanoma of skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine

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

0.84

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

T;T;T

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Uncertain

-0.21

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.5

D;.;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.010

D;T;D

Polyphen

1.0

D;.;.

Vest4

0.80

MutPred

0.63

Gain of MoRF binding (P = 0.0204);Gain of MoRF binding (P = 0.0204);Gain of MoRF binding (P = 0.0204);

MVP

0.91

MPC

1.3

ClinPred

0.97

GERP RS

4.9

Varity_R

0.72

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over