rs104894109

Positions:

• chr9-21971192-C-A
• chr9-21971192-C-G
• chr9-21971192-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.167G>T​(p.Ser56Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 0.134

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 12 ACMG points.

• PM1: In a repeat ANK 2 (size 28) in uniprot entity CDN2A_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971192-C-A is Pathogenic according to our data. Variant chr9-21971192-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.167G>T	p.Ser56Ile	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.210G>T	p.Gln70His	missense_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.167G>T	p.Ser56Ile	missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.210G>T	p.Gln70His	missense_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445436 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719506

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 16, 2018

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The p.S56I pathogenic mutation (also known as c.167G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 167. The serine at codon 56 is replaced by isoleucine, an amino acid with dissimilar properties. The p.S56I alteration has been reported in numerous individuals with personal and/or family histories consistent with multiple primary melanoma (Begg CB et al. J. Natl. Cancer Inst., 2005 Oct;97:1507-15; Bishop DT et al. J. Natl. Cancer Inst., 2002 Jun;94:894-903; Chaudru V et al. Cancer Epidemiol. Biomarkers Prev., 2005 Oct;14:2384-90; Kannengiesser C et al. Genes Chromosomes Cancer, 2007 Aug;46:751-60; Landi MT et al. J. Med. Genet., 2004 Jul;41:557-66; Soufir N et al. Hum. Mol. Genet., 1998 Feb;7:209-16; Pellegrini C et al. Melanoma Res., 2017 06;27:258-267). This alteration has also been reported as a suggested founder mutation in individuals of French and Italian background as many patients who carry the p.S56I alteration share a unique haplotype (Kannengiesser C et al. Genes Chromosomes Cancer, 2007 Aug;46:751-60). One functional analysis of this alteration indicated retained ability to bind CDK6 at least as well as the wild-type protein but showed diminished affinity for CDK4 (McKenzie HA et al. Hum. Mutat., 2010 Jun;31:692-701). An additional functional analysis using a cell cycle arrest assay indicated p.S56I results in in vitro function loss (Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11). Further, this alteration has been shown to bind CDK4 very poorly compared to the wild-type in a yeast based two-hybrid assay (Monzon J et al. N. Engl. J. Med., 1998 Mar;338:879-87). In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2023

The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 56 of the CDKN2A (p16INK4a) protein (p.Ser56Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cutaneous malignant melanoma and/or primary melanoma (PMID: 9425228, 9516223, 12072543, 15150307, 15235029, 17492760, 21462282, 22841127). It has also been observed to segregate with disease in related individuals. This variant is also known as c.210G>T (p.Gln70His) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 9425). 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: 9516223, 20340136, 21462282, 25370744). For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. -

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

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.42	.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.50	T
PROVEAN	Uncertain	-4.1	.;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.0060	D;D
Vest4		0.40
MVP		0.96
ClinPred		0.99	D
GERP RS		0.26

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: rs104894109; hg19: chr9-21971191;