rs104894099

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP4

The NM_000077.5(CDKN2A):c.176T>G(p.Val59Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,444,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 6.84

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:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 9-21971183-A-C is Pathogenic according to our data. Variant chr9-21971183-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.2724597). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5 link	c.176T>G	p.Val59Gly	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 link	c.219T>G	p.Ser73Arg	missense_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2	Q8N726-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 link	c.176T>G	p.Val59Gly	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5		P42771-1
CDKN2A	ENST00000579755.2 link	c.219T>G	p.Ser73Arg	missense_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000456

AC:

AN:

219096

Hom.:

AF XY:

0.00

AC XY:

AN XY:

122126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

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:

0.00000208

AC:

AN:

1444950

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

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:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000838

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKN2A: PP1:Strong, PM2, PS4:Moderate, PS3:Supporting, BP4 -

Jan 26, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported as individuals and families with melanoma and pancreatic cancer in the published literature (PMID: 9425228 (1998), 22841127 (2012), 26681309 (2016), 29506128 (2018), 29543703 (2018), and 32113160 (2020)). A peer-reviewed experimental study has reported a damaging effect of the variant on p16 protein function (PMID: 12700603 (2003)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. Based on the available information, this variant is classified as pathogenic. -

Aug 29, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: reduced binding with CDK4 and CDK6 and a moderate impact on cell proliferation (Yacobson et al., 2003; Kannengiesser et al., 2009); This variant is associated with the following publications: (PMID: 15150307, 29506128, 9425228, 25780468, 19571771, 26681309, 21893440, 19260062, 22841127, 19799798, 10874641, 15860862, 16905682, 12700603, 9823374, 28873162, 28717660, 15146471, 16470311, 17492760, 17055252, 29543703, 31589614, 33237286, 28979722, 20653773, 32113160, 34072659, 33322357) -

Melanoma-pancreatic cancer syndrome

Pathogenic:2

Aug 10, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2024

Genetics Department, Catlab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.176T>G variant in the CDKN2A gene has been previously found in at least 4 independent families with several affected members where it segregated (PMID:12700603) (PS4_Moderate, PP1) and the variant has an extremely low frequence in gnomAD 4.0 (AF= 1.8e-06) (PM2). Functional studies have shown that the variant alters the function of p16INK4a (PMID: 12700603) (PS3_Moderate). The REVEL value is 0.189 (BP4). With all the available evidence, the variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Aug 03, 2023

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 valine with glycine at codon 59 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 have shown the mutant protein to exhibit defective binding to CDK4 and CDK6, and reduced ability to suppress cell proliferation (PMID: 12700603, 19260062). This variant has been observed in many individuals and families affected with melanoma (PMID: 9036865, 9425228, 10874641, 12700603, 14646620, 19260062, 19571771, 20653773, 21893440, 22841127, 25780468, 26681309, 29543703, 32455486, 35566480) and shown to segregate with melanoma in three unrelated families (PMID: 12700603). This variant has also been reported in an individual affected with familial pancreatic cancer (PMID: 32113160). This variant has been identified in 1/219096 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jun 19, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V59G variant (also known as c.176T>G), located in coding exon 2 of the CDKN2A gene, results from a T to G substitution at nucleotide position 176. The valine at codon 59 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in several families with multiple cases of melanoma and/or pancreatic cancer (Puig S et al. J. Clin. Oncol. 2005 May;23:3043-51; Pedace L et al. Cancer Epidemiol. 2011 Dec;35:e116-20; Nagore E et al. Melanoma Res. 2009 Aug;19:211-4; Goldstein AM et al. J. Med. Genet. 2007 Feb;44:99-106; Earl J et a. EBioMedicine 2020 Mar;53:102675; De Simone P et al. Int J Mol Sci, 2020 Dec;21:). One study described this alteration in four families with multiple cases of melanoma and determined that it may be a founder mutation of Mediterranean origin (Yakobson E et al. Eur. J. Hum. Genet. 2003 Apr;11:288-96). Based on the results of protein–protein interaction and cell proliferation assays, the authors concluded that this alteration likely impairs p16 protein function, but may be only a moderate dysfunction mutation. Notably, there were several unaffected p.V59G carriers identified in these four families. In addition, one individual diagnosed with melanoma at age 36 was found to be homozygous for this alteration (Yakobson E et al. Eur. J. Hum. Genet. 2003 Apr;11:288-96). This alteration has also been reported in pancreatic cancer patients (Lowery MA et al. J. Natl. Cancer Inst., 2018 10;110:1067-1074; Earl J et al. EBioMedicine, 2020 Mar;53:102675), including in a patient with a rare tumor type of adenosquamous pancreatic carcinoma (ASPC) (Martínez de Juan F et al. World J Gastrointest Oncol. 2017 Sep;9:390-396). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial melanoma

Pathogenic:2

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 59 of the CDKN2A (p16INK4a) protein (p.Val59Gly). This variant is present in population databases (rs104894099, gnomAD 0.003%). This missense change has been observed in individuals with melanoma (PMID: 9425228, 12700603, 15146471, 19571771, 19799798, 20653773, 21893440, 22841127, 26681309). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9423). 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: 12700603). For these reasons, this variant has been classified as Pathogenic. -

Jul 18, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDKN2A c.176T>G (p.Val59Gly) results in a non-conservative amino acid change located in the second ankyrin repeat domain (Soufir_1998) of 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 4.6e-06 in 219096 control chromosomes. c.176T>G has been reported in the literature in multiple individuals from families affected with sporadic/Cutaneous Malignant Melanoma ((example, Piccinin_1997, Soufir_1998, Yakobson_2003, Puig_2005, Casula_2007, de Torre_2010, De Unamuno_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in-vitro (example, Yakobson_2003). The most pronounced variant effect results in moderate levels of dysfunction as measured by ability to interact with CDK4 and CDK6 as well as its ability to inhibit the proliferation of human diploid fibroblasts. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Melanoma, cutaneous malignant, susceptibility to, 2

Pathogenic:1Other:1

Apr 01, 2003

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 20, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma and neural system tumor syndrome

Pathogenic:1

Jan 13, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Dec 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.0071

T;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.31

.;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.86

PROVEAN

Benign

-1.0

.;N

REVEL

Benign

0.19

Sift

Benign

0.29

.;T

Sift4G

Benign

0.43

T;T

Vest4

0.31

MVP

0.99

ClinPred

0.81

GERP RS

4.7

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

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