rs199907548

Variant names:

• chr9-21974682-A-C
• rs199907548
• NM_000077.5:c.146T>G

Your query was ambiguous. Multiple possible variants found:

• chr9-21974682-A-C
• chr9-21974682-A-G
• chr9-21974682-A-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.146T>G​(p.Ile49Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,744 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I49T) has been classified 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:7
• Conservation: PhyloP100: 5.56
• Publications: 38 publications found

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 Gene-Disease associations (from GenCC):

• melanoma, cutaneous malignant, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• melanoma-pancreatic cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atypical multiple mole melanoma syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma and neural system tumor syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 47 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 chr9-21974682-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127523.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 9-21974682-A-C is Pathogenic according to our data. Variant chr9-21974682-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 430217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.146T>G	p.Ile49Ser	missense_variant	Exon 1 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3474T>G		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.146T>G	p.Ile49Ser	missense_variant	Exon 1 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194-3474T>G		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461744 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma-pancreatic cancer syndrome Pathogenic:2

Sep 16, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20340136, 10719365]. 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: 21462282, 10667595, 10398427, 22841127]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 08, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces isoleucine with serine at codon 49 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant causes a partial loss of protein function, as shown by subcellular mislocalization and decreased binding to CDK4 and CDK6 (PMID: 10719365, 20340136). This variant has been reported in five individuals affected with familial melanoma (PMID: 10398427, 12072543, 17218939, 22841127, 28830827) and in an individual affected with both melanoma and pancreatic cancer. (PMID: 10719365). In one family, this variant was observed in three siblings affected with melanoma (PMID: 10398427). This variant has also been reported in an individual with liposarcoma with a history of osteosarcoma in a first-degree relative (PMID: 28592523). 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 Likely Pathogenic. -

Jan 07, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I49S pathogenic mutation (also known as c.146T>G), located in coding exon 1 of the CDKN2A gene, results from a T to G substitution at nucleotide position 146. The isoleucine at codon 49 is replaced by serine, an amino acid with dissimilar properties. This alteration has been identified in numerous familial melanoma cohorts, as well as in an individual with both melanoma and pancreatic cancer (Ambry internal data; Holland EA et al. Genes Chromosomes Cancer. 1999 Aug;25:339-48; Lal G et al. Genes Chromosomes Cancer. 2000 Apr;27:358-61; Begg CB et al. J. Natl. Cancer Inst. 2005 Oct;97:1507-15; Goldstein AM et al. J. Med. Genet. 2007 Feb;44:99-106; Miller PJ et al. Hum. Mutat. 2011 Aug;32:900-11; Maubec E et al. J. Am. Acad. Dermatol. 2012 Dec;67:1257-64). In addition, this alteration demonstrated defective CDK4 and CDK6 binding as well as increased rates of proliferation and abnormal subcelluar staining patterns (Lal G et al. Genes Chromosomes Cancer. 2000 Apr;27:358-61; McKenzie HA et al. Hum. Mutat. 2010 Jun;31:692-701). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Melanoma and neural system tumor syndrome Pathogenic:1

Dec 28, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 07, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The I49S variant has been published previously in association with melanoma (Holland et al., 1999; Begg et al., 2005; Goldstein et al., 2007; Lag et al, 2000). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. I49S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position located within the ANK2 domain where amino acids with similar properties to isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (P48L, Q50R, V51F, M53V/T/I, M54I) have been reported in the Human Gene Mutation Database in association with melanoma (Stenson et al., 2014), supporting the functional importance of this region of the protein. Functional studies of the I49S variant have demonstrated that it results in reduced binding activity, altered localization, and increased proliferation in comparison to the wild type (Lal et al., 2000; McKenzie et al., 2010). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Familial melanoma Pathogenic:1

Nov 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 49 of the CDKN2A (p16INK4a) protein (p.Ile49Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic adenocarcinoma and/or melanoma (PMID: 10398427, 10719365, 22841127, 28830827). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 430217). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 10719365, 20340136). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;D;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	-0.059	T
PhyloP100		5.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.7	D;.;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.87
MutPred		0.72		Gain of disorder (P = 0.0017);Gain of disorder (P = 0.0017);Gain of disorder (P = 0.0017);
MVP		0.98
MPC		1.5
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		-0.025	Neutral
Varity_R		0.74
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199907548; hg19: chr9-21974681; COSMIC: COSV58696067; COSMIC: COSV58696067;