9-21970982-A-T

Position:

• chr9-21970982-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.377T>A​(p.Val126Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,484 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 6.75

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 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, 0.978
• PP5: Variant 9-21970982-A-T is Pathogenic according to our data. Variant chr9-21970982-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 9420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21970982-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.377T>A	p.Val126Asp	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.*21T>A		3_prime_UTR_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.377T>A	p.Val126Asp	missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755	c.*21T>A		3_prime_UTR_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458484 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725704

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma-pancreatic cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 20, 2024	Criteria applied: PS3,PS4,PM2_SUP,PP1,PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 20, 2023	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7987387, 7987388]. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 11, 2021	The CDKN2A c.377T>A (p.Val126Asp) missense change replaces valine with aspartic acid at codon 126 of the CDKN2A gene and is absent in population databases including gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). This variant is one of the most common pathogenic variants found in melanoma-prone families (PMID: 21249757). It has been reported in over twenty individuals affected with familial melanoma (PS4; PMID: 9425228, 11506491, 20340136, 21614589, 23371019, 25685612, 26225579) and been shown to segregate with disease in two families affected with melanoma (PP1; PMID: 7987387). In addition, it has been reported in multiple individuals affected with pancreatic cancer (PMID: 15146471, 25356972, 29541281) and in an individual with osteosarcoma where the tumor was found to be homozygous for the variant (PP4; internal data). Five of six in silico tools predict a deleterious effect of this variant on protein function (PP3), and in vitro functional assays have shown that this variant impairs cell cycle inhibition and binding affinity to CDK4 and CDK6 (PS3; PMID: 7566978, 7647780, 8668202, 11595726, 20340136, 21462282, 23190892). This variant is also known as p.Val118Asp in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied: PS3, PS4, PM2_supporting, PP1, PP3, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 13, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 22, 2022	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with melanoma and pancreatic cancer (PMIDs: 22841127 (2012), 18983535 (2008), 16905682 (2007), 15146471 (2004), 9425228 (1998)). Functional studies showed that the variant impacts protein function (PMIDs: 23190892 (2013), 20340136 (2010), 11595726 (2001), 10389768 (1999)). Additionally, the variant has been reported to segregate with melanoma in several affected families (PMID: 7987387 (1994)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2022	Published functional studies demonstrate a damaging effect: impaired cell cycle inhibition, sub-cellular localization, and CDK4 and CDK6 binding (Parry 1996, Becker 2001, McKenzie 2010, Miller 2011, Jenkins 2013); 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); Also known as Val118Asp; This variant is associated with the following publications: (PMID: 9425228, 15146471, 15304099, 23371019, 10389768, 23190892, 7566978, 11595726, 21462282, 7987388, 7666916, 11506491, 11008905, 16905682, 16893909, 12925390, 11807902, 17492760, 26694476, 20340136, 7647780, 8668202, 27473757, 28060055, 25356972, 29541281, 29215650, 30113427, 31567591, 22841127, 18983535, 26225579, 33555482, 33766116, 34573422, 16169933, 7987387) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 14, 2022	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces valine with aspartic acid at codon 126 in the fourth ankyrin repeat of the CDKN2A (p16INK4A) protein. This variant is also known as p.Val118Asp in the literature. 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 have shown that this variant impairs p16INK4A binding to CDK4 and CDK6 (PMID: 7647780, 8668202, 11595726, 20340136) and disrupts subcellular localization (PMID: 10389768, 20340136), and cell cycle regulation (PMID: 8668202, 11595726, 20340136, 23190892, 35001868). This variant has been reported in over twenty individuals affected with familial melanoma (PMID: 9425228, 11506491, 20340136, 26225579, 21614589, 23371019, 25685612) and in over ten individuals affected with pancreatic cancer (PMID: 15146471, 25356972, 29541281). This variant has been shown to segregate with disease in two families affected with melanoma (PMID: 7987387). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 12, 2024	The p.V126D pathogenic mutation (also known as c.377T>A), located in coding exon 2 of the CDKN2A gene, results from a T to A substitution at nucleotide position 377. The valine at codon 126 is replaced by aspartic acid, an amino acid with highly dissimilar properties. Data supports p.V126D as a North American founder mutation (Goldstein AM et al. Br. J. Cancer, 2001 Aug;85:527-30). It is well documented in families with hereditary melanoma (Hussussian CJ et al. Nat. Genet. 1994 Sep;8(1):15-21; Parry D and Peters G. Mol. Cell. Biol. 1996 Jul;16(7):3844-52; Walker GJ et al. Int. J. Cancer. 1999 Jul;82:305; Becker TM et al. Clin. Cancer. Res. 2001 Oct;7:3282; Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11) and has also been identified in a familial pancreatic cancer kindred with no melanoma history (Cremin C et al. Hered Cancer Clin Pract, 2018 Mar;16:7). Functional studies have shown this alteration exhibits significantly decreased CDK4/CDK6 affinity and impaired cell cycle regulation (Ranade K et al. Nat. Genet. 1995 May;10(1):114-6; McKenzie HA et al. Hum. Mut. 2010 Jun;31(6):692-701; Jenkins NC et al. J. Invest. Dermatol. 2013 Apr;133(4):1043-51). Of note, this alteration is also designated as p.Val118Asp (p.V118D) in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial melanoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 05, 2022	Variant summary: CDKN2A c.377T>A (p.Val126Asp), also known as p.Val118Asp, 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 was absent in 244452 control chromosomes (gnomAD). c.377T>A has been reported in the literature segregating with disease in multiple individuals affected with Malignant Melanoma (e.g. Kamb_1994, Hussussian_1994). These data indicate that the variant is very likely to be associated with disease. In vitro assays revealed that the variant had reduced binding affinity and ability to inhibit cyclin D1/CDK4 activity, and complete inability to bind/inhibit cyclin D1/CDK6 activity (Ranade_1995). Additionally, transcriptomic analysis of skin fibroblasts revealed there were consistent shifts in gene expression profiles between carriers and controls (Fan_2013). Six ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 126 of the CDKN2A (p16INK4a) protein (p.Val126Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 7987387, 9425228, 15146471, 16905682, 20340136, 23371019, 25356972). It has also been observed to segregate with disease in related individuals. This variant is also known as Val118Asp. ClinVar contains an entry for this variant (Variation ID: 9420). 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: 7647780, 8668202, 10389768, 11595726, 20340136, 23190892). For these reasons, this variant has been classified as Pathogenic. -

Melanoma and neural system tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 25, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 24, 2021

- -

Melanoma, cutaneous malignant, susceptibility to, 2 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Uncertain	0.55	D;T;.;.;.;.;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;T;.;D;.;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.0095	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.2	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.85
MutPred		0.74		Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);.;Gain of disorder (P = 0.0081);.;.;.;.;
MVP		1.0
MPC		1.6
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.90

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: rs104894098; hg19: chr9-21970981; COSMIC: COSV58684293; COSMIC: COSV58684293;