rs104894094

chr9-21971058-C-Achr9-21971058-C-Gchr9-21971058-C-T

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: CDKN2A NM_000077 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 0.816

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_000077
• PM2: Very rare variant; Number of alleles below threshold, gnomad allele frequency = 0.0000131 (2/152228) while in subpopulation NFE AF= 0.0000294 (2/68044). AF 95% confidence interval is 0.00000488. There are 0 homozygotes in gnomad. There are 0 alleles in male gnomad subpopulation. Median coverage is 32. This position pass quality control queck.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 9:21971058-C>A is Pathogenic according to our data. Variant chr9-21971058-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 9412. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21971058-C-A is described in Lovd as [Pathogenic]. Variant chr9-21971058-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.301G>T	p.Gly101Trp	missense_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.344G>T	p.Arg115Leu	missense_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.301G>T	p.Gly101Trp	missense_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.344G>T	p.Arg115Leu	missense_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1452982 Hom.: 0 AF XY: 0.00000277 AC XY: 2 AN XY: 723122

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: 0.00000900

Gnomad4 OTH exome AF: 0.00

Alfa AF: 0.0000294 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	Criteria applied: PP1:Strong, PM1, PM2, PS4:Moderate, PS3, BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 17, 2017	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Statistically associated with disease in multiple families. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2023	Reported in association with familial melanoma and pancreatic cancer, and is a common pathogenic founder variant observed to segregate with disease in numerous geographically-diverse families (Hussussian et al., 1994; Whelan et al., 1995; Ciotti et al., 2000; Mantelli et al., 2002; Ghiorzo et al., 2004; Ghiorzo et al., 2007; Bruno et al., 2009; Bruno et al., 2016; Puig et al., 2016); Published functional studies demonstrate a damaging effect: impaired cell cycle inhibition and CDK4 and CDK6 binding (Ranade et al., 1995; Yang et al., 1995; Parry and Peters, 1996; Gombart et al., 1997; Kannengiesser et al., 2009; McKenzie et al., 2010; Miller et al., 2011; Scaini et al., 2014); 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; This variant in the p16 isoform also results in a variant of uncertain significance in the p14-ARF protein, c.344G>T (p.Arg115Leu); This variant is associated with the following publications: (PMID: 22804906, 19158841, 26225579, 27181379, 25787093, 22841127, 26650572, 25970827, 28146043, 28452926, 28726808, 7780957, 7777061, 8668202, 9324288, 10389768, 19260062, 20340136, 21462282, 18024887, 10869234, 17167857, 25780468, 15235029, 15140239, 10874641, 25803691, 7987388, 19500876, 7566978, 14679123, 7647780, 24659262, 7987387, 19360740, 15860862, 11807902, 26681309, 22368299, 25023876, 25431349, 26775776, 26800492, 26892652, 26650189, 27473757, 26658419, 28060055, 26381259, 28030792, 28592523, 27926368, 29464027, 20653773, 7666917, 29543703, 30113427, 30338612, 31432501, 11243640, 12001124, 27960642, 21801156, 8012957, 16818274, 27756164, 9166859, 9425228, 15146471, 11579459, 8552158, 7718873, 29922827, 32482799, 18519632, 35123577, 31628766, 30218143, 30291219, 28765326) -

Melanoma-pancreatic cancer syndrome Pathogenic:5

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: 11556834, 17047042]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Apr 06, 2018	- -

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

risk factor, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 05, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2021	This missense variant replaces glycine with tryptophan at codon 101 in the ankyrin repeat motif of the CDKN2A (p16INK4A) protein. This variant is also known as p.Gly93Trp in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs the ability of p16INK4A protein to bind CDK4 and CDK6 and control cell cycle (PMID: 7566978, 7647780, 9324288, 19260062, 20340136, 21462282, 24659262). This variant has been reported in numerous individuals affected with melanoma and pancreatic cancer (PMID: 9425228, 11579459, 12072543, 14679123, 15146471, 15860862, 16234564, 19360740, 20340136, 21801156, 22841127, 25780468, 26381259, 26658419, 26681309, 26775776, 27181379, 28146043, 29464027, 29945567, 30274933, 31432501, 31517177, 32455486). This variant has been shown to segregate with disease in many families (PMID: 7666917, 7987387, 8552158, 9425228, 10508477) and is thought to be a European founder mutation (PMID: 10869234, 11579459, 15860862). 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	Jun 07, 2021	The p.G101W pathogenic mutation (also known as c.301G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 301. The glycine at codon 101 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in numerous individuals diagnosed with FAMMM (Whelan AJ et al. N. Engl. J. Med. 1995 Oct;333:975-7; Ranade K et al. Nat. Genet.,1995 May;10:114-6; Gironi LC et al. Int. J. Dermatol. 2015 Dec;54:e553-5; Roberts NJ et al. Cancer Discov. 2016 Feb;6:166-75). It has also been reported as one of the most common CDKN2A mutations (Vinarsky V et al. Head Neck. 2009;31:1524-7; Puig S et al. Genet Med, 2016 07;18:727-36). In one meta-analysis, 9 of 22 families with this mutation reported at least one case of pancreatic cancer (Goldstein AM et al. Hum. Mutat. 2004; 23:630). Several functional studies have revealed a significant decrease in the ability of p.G101W to inhibit cell growth (Walker GJ et al. Int. J. Cancer. 1999;82:305-12; Miller PJ et al. Hum. Mutat. 2011;32:900-11). In addition, while some studies have shown that the mutant protein maintains some ability to bind with CDK4, additional studies have demonstrated that the binding affinity is temperature dependent, with 75% of binding affinity compared to wildtype at 30 degrees Celsius, but <10% of binding affinity compared to wildtype at 42 degrees Celsius (Walker GJ et al. Int. J. Cancer. 1999;82:305-12; Kannengiesser C et al. Hum. Mutat. 2009;30:564-74; Parry D et al. Mol. Cell. Biol. 1996 Jul;16(7):3844-52). Further, mass spectrometry analysis of this alteration indicates a significantly altered structure, and in silico molecular dynamics simulations predict that this alteration creates a misfolding of the third and fourth ankryin repeats, with a partial conservation of the first and second repeats at the binding site, which explains its partial retention of CDK4 binding in vitro but its inability to block cell proliferation (Tevelev A et al. Biochemistry. 1996 Jul;35(29):9475-87; Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). The partially folded state is predicted to promote faster degradation, resulting in a decreased half-life of the protein and a higher tendency to form protein aggregates (Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). Of note, this pathogenic mutation has also been reported in the literature as p.G93W (c.295G>T). 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	Invitae	Oct 19, 2022	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 glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 101 of the CDKN2A (p16INK4a) protein (p.Gly101Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and pancreatic cancer (PMID: 10869234, 11807902, 14679123, 15146471, 21462282, 21801156). It has also been observed to segregate with disease in related individuals. This variant is also known as c.344G>T (p.Arg115Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 9412). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 20340136, 21462282). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 12, 2022	Variant summary: CDKN2A c.301G>T (p.Gly101Trp) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234668 control chromosomes (gnomAD, Kamb_1994). c.301G>T has been reported in the literature in multiple individuals affected with Melanoma (e.g. Kamb_1994, Hussussian_1994, Blackwood_2002). These data indicate that the variant is very likely to be associated with disease. . Kannengiesser_2008 reports that the variant causes a loss of CDK4 binding which results in aberrant proliferation in cell culture. This was was confirmed by Miller_2011, who showed that in a cell cycle arrest assay, the variant caused a complete loss of cell cycle arrest. Twelve 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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2014

- -

Melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 18, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.40

D

BayesDel_noAF

Uncertain

-0.070

Cadd

Uncertain

25

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.67

D;T;.;.;.;.;T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.92

D

LIST_S2

Uncertain

0.94

D;D;.;D;.;D;D;D

M_CAP

Pathogenic

0.62

D

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.041

D

MutationTaster

Benign

0.82

D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.51

T

PROVEAN

Pathogenic

-6.1

D;.;.;D;.;.;.;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

D;.;.;D;.;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;.;.

Vest4

0.77

MutPred

0.83

Gain of MoRF binding (P = 0.0329);Gain of MoRF binding (P = 0.0329);.;Gain of MoRF binding (P = 0.0329);.;.;.;.;

MVP

0.99

MPC

1.3

ClinPred

0.88

D

GERP RS

5.9

Varity_R

0.53

gMVP

0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894094; hg19: chr9-21971057; COSMIC: COSV58692144; COSMIC: COSV58692144;