rs768966657

chr9-21971021-A-AGAC

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000077.5(CDKN2A):c.337_338insGTC(p.Arg112dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00000344 in 1,455,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L113L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CDKN2A NM_000077.5 inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.00

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000077.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-21971021-A-AGAC is Pathogenic according to our data. Variant chr9-21971021-A-AGAC is described in ClinVar as [Pathogenic]. Clinvar id is 183759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.337_338insGTC	p.Arg112dup	inframe_insertion	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.380_381insGTC	p.Ser127_Ala127insSer	inframe_insertion	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.337_338insGTC	p.Arg112dup	inframe_insertion	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.380_381insGTC	p.Ser127_Ala127insSer	inframe_insertion	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000126 AC: 3 AN: 238418 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130554

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000277

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1455010 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724106

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2022	In-frame insertion of 1 amino acid located in the critical ANK 4 repeat (UniProt); Identified in several malignant melanoma families and published as a Swedish founder pathogenic variant (Borg et al., 1996; Platz et al., 1997; Borg et al., 2000; Hashemi et al., 2000; Hashemi et al., 2001; Goldstein et al., 2006; Helgadottir et al., 2014; Helgadottir et al., 2020); Case control studies suggest this variant is associated with increased risk for melanoma, pancreatic cancer, and possibly other cancers (Helgadottir et al., 2014); Published functional studies demonstrate a damaging effect: inability to bind CDK4 and CDK6 (Ruas et al., 1999; Borg et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 113insArg and c.337-338insGTC; This variant is associated with the following publications: (PMID: 10498896, 10922411, 9168184, 10338331, 16905682, 8653684, 24935963, 12072543, 17047042, 15146471, 19077144, 11319798, 11156381, 27287845, 29215650, 33076392, 33945383, 33766116, 30291219, 29922827) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 13, 2019	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2021	This variant is a 3 nucleotide duplication located in exon 2 of the CDKN2A (p16INK4A) gene, creating a single amino acid duplication in the CDKN2A protein. Functional studies have shown that this variant impairs the binding to CDK4 and CDK6 in vitro (PMID: 10498896, 10922411). This variant has been reported in individuals affected with melanoma and is a frequently observed mutation in melanoma-prone families from Northern Europe (PMID: 8653684, 9168184, 10922411, 11156381, 11319798, 12072543, 16905682, 15146471, 17047042, 20526219, 24935963, 25803691, 25813228, 8653684, 9168184, 11319798). It has been shown that this variant segregates with disease and is reported as a Swedish founder mutation in melanoma-prone families (PMID: 8653684, 9168184, 11319798). Carrier families are also prone to non-melanoma cancer including breast and pancreatic carcinomas (PMID: 10922411, 15146471, 17047042, 24935963). This variant has been identified in 3/238418 chromosomes 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	Feb 26, 2024	The c.335_337dupGTC pathogenic mutation (also known as p.R112dup) located in coding exon 2 of the CDKN2A gene, results from an in-frame duplication of GTC between nucleotide positions 335 and 337. This results in the duplication of an arginine residue at codon 112. This alteration has been described as one of the most common CDKN2A mutations in Europe and as a founder mutation in the Swedish population (Borg et al. Cancer Res. 1996; 56(11): 2497-500; Goldstein AM et al. Cancer Res., 2006 Oct;66:9818-28;Goldstein AM. Hum. Mutat., 2004 Jun;23:630; Goldstein AM, J. Med. Genet. 2007 Feb; 44(2):99-106; Hashemi J, et al. Genes Chromosomes Cancer 2001 Jun; 31(2):107-16; Nielsen K et al. Melanoma Res., 2010 Aug;20:266-72; Helgadottir H et al. J. Natl. Cancer Inst., 2016 Nov;108:). This alteration is located in the functionally-important ankyrin repeat region and has been shown to result in loss of binding capacity for cdk4 and cdk6 in vitro (Ruas M, et al. Oncogene 1999 Sep; 18(39):5423-34; Borg A, J. Natl. Cancer Inst. 2000 Aug; 92(15):1260-6). Based on a study of 28 Swedish families with the c.335_337dupGTC mutation, carriers are estimated to have increased relative risk compared to non-carrier controls for melanoma (RR = 64.8) and pancreatic cancer (RR = 43.8), as well as malignancies of the upper digestive (RR = 17.1) and respiratory tract (RR = 15.6) (Helgadottir H, et al. J. Med. Genet. 2014 Aug; 51(8):545-52). Overall risks for these cancer types were increased further for ever-smoker carriers compared to never-smoker carriers in this study (OR = 9.3). Of note, this alteration is also known as p.R112_L113insR, p.Arg105ins, 113insArg, and 337-338insGTC in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Melanoma and neural system tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 20, 2022

- -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

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 variant, c.335_337dup, results in the insertion of 1 amino acid(s) of the CDKN2A (p16INK4a) protein (p.Arg112dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs768966657, gnomAD 0.003%). This variant has been observed in individuals with melanoma and/or pancreatic cancer (PMID: 8213823, 8653684, 11319798, 24935963, 30291219; Invitae). It is commonly reported in individuals of Swedish ancestry (PMID: 865368, 11319798). This variant is also known as 113insR, 113insArg, p.R112_L113insR, 112-113insArg, c.337_338insGTC in the CDKN2A (p16INK4a) transcript, and c.378_380dup (p.Ser127dup) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 183759). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CDKN2A (p16INK4a) function (PMID: 10922411). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs768966657; hg19: chr9-21971020;