rs373291490

chr9-21970994-C-Achr9-21970994-C-Gchr9-21970994-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PM1 PP3_Strong BP6 BS2

The NM_000077.5(CDKN2A):c.365G>T(p.Gly122Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,609,606 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G122R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: 4.20

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in NM_000077.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• BP6: Variant 9-21970994-C-A is Benign according to our data. Variant chr9-21970994-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182419.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=7}.
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.365G>T	p.Gly122Val	missense_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.*9G>T		3_prime_UTR_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.365G>T	p.Gly122Val	missense_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.*9G>T		3_prime_UTR_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes AF: 0.000144 AC: 22 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000330 AC: 8 AN: 242764 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132408

Gnomad AFR exome AF: 0.000448

Gnomad AMR exome AF: 0.0000291

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: 0.0000110 AC: 16 AN: 1457356 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725218

Gnomad4 AFR exome AF: 0.000329

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74374

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2023	Observed in individuals with melanoma or pancreatic cancer, but also in unaffected controls (Yakobson et al., 2000; Miller et al., 2011; Taylor et al., 2017; McWilliams et al., 2018); Published functional studies are conflicting: while some demonstrate a damaging effect with reduced binding to CDK4 and reduced ability to inhibit cell proliferation, others demonstrate neutral cell proliferation effects (Yakobson et al., 2000; Miller et al., 2011; Kimura et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant in the p16 isoform also results in a variant of uncertain significance in the p14-ARF protein, c.*9G>T; This variant is associated with the following publications: (PMID: 9806478, 15146471, 10596908, 21462282, 10951521, 15609895, 15863662, 24185512, 30039340, 35001868, 30038052, 28830827, 33237286) -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 05, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 03, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 31, 2022	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 28, 2020

Variant summary: CDKN2A c.365G>T (p.Gly122Val) 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 allele was found at a frequency of 4.1e-05 in 244676 control chromosomes, predominantly at a frequency of 0.00045 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.365G>T has been reported in the literature in individuals affected with Malignant Melanoma (example: Yakobson_2000, Taylor_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. In in vitro functional studies, the variant partially reduced CDKN2A function (Yakobson_2000, Miller_2011). Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Melanoma and neural system tumor syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 17, 2023

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Melanoma-pancreatic cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Oct 04, 2022

The CDKN2A c.365G>T (p.Gly122Val) missense change has a maximum subpopulation frequency of 0.053% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in the literature in an individual with a personal and family history of melanoma (PMID: 10951521). The in silico tool REVEL predicts a deleterious effect on protein function. Functional studies have demonstrated a reduced ability to bind to CDK4 and impaired ability to cause cell cycle arrest (PMID: 10951521, 21462282). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.s -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 122 of the CDKN2A (p16INK4a) protein (p.Gly122Val). This variant is present in population databases (rs373291490, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma or pancreatic cancer (PMID: 10951521, 21462282, 30038052). ClinVar contains an entry for this variant (Variation ID: 182419). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 10951521, 21462282, 35001868). 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	0.24	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;T;.;.;.;.;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.2	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.74
MVP		1.0
MPC		1.4
ClinPred		0.78	D
GERP RS		5.9
Varity_R		0.66
gMVP		0.79

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: rs373291490; hg19: chr9-21970993; COSMIC: COSV58689831; COSMIC: COSV58689831;