Submissions for variant NM_000077.5(CDKN2A):c.225_243del (p.Ala76fs)

dbSNP: rs730881674

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160405	SCV000210937	pathogenic	not provided	2022-02-21	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of CDK4/CDK6 binding, loss of cell cycle inhibitory activity, and altered subcellular localization (McKenzie 2010); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p16-Leiden and considered a Dutch founder variant; This variant is associated with the following publications: (PMID: 16905682, 29961768, 25227142, 12549483, 23897584, 10956390, 22636603, 9579547, 7640518, 26111702, 27406244, 11815963, 21570156, 12690301, 26670666, 27267843, 27672215, 18813118, 18981015, 15146471, 28592523, 29316957, 29263814, 29769629, 30113427, 31923587, 32953120, 32482799, 31203567, 20340136)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000161946	SCV000211931	pathogenic	Familial melanoma	2020-09-08	criteria provided, single submitter	clinical testing	The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. This sequence change deletes 19 nucleotides from exon 2 of the CDKN2A (p16INK4a) mRNA (c.225_243del), causing a frameshift at codon 76. This creates a premature translational stop signal within the last 15 codons of the penultimate exon of the CDKN2A (p16INK4a) mRNA (p.Ala76Cysfs*64). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acids of the CDKN2A (p16INK4a) protein. Alternatively, this sequence change deletes 19 nucleotides from exon 2 of the CDKN2A (p14ARF) mRNA (c.268_286del), causing a frameshift at codon 90. This extends reading frame beyond the termination signal of the CDKN2A (p14ARF) mRNA (p.Arg90Valfs*76). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acids of the CDKN2A (p14ARF) protein. This particular variant, also known as the p16-Leiden variant in the literature, has been reported in numerous families and individuals affected with pancreatic cancer, cutaneous malignant melanoma, and familial atypical multiple mole melanoma and is considered to be a Dutch founder mutation (PMID: 22636603, 20340136, 23897584, 17047042, 16905682, 109563903, 7640518). ClinVar contains an entry for this variant (Variation ID: 182411). Experimental studies have shown that this variant affects p16INK4a protein localization and reduces p16INK4a binding affinity to CDK4 and CDK6 (PMID: 20340136). Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000493242	SCV000581507	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	clinical testing	The c.225_243del19 pathogenic mutation, located in coding exon 2 of the CDKN2A gene, results from a deletion of 19 nucleotides at nucleotide positions 225 to 243, causing a translational frameshift with a predicted alternate stop codon (p.A76Cfs*64). This mutation has been reported in numerous individuals and families with personal and/or family history consistent with familial atypical multiple mole melanoma (FAMMM) syndrome (Gruis NA et al. Melanoma Res. 1995 Jun;5:169-77; Holland EA et al. Genes Chromosomes Cancer, 1999 Aug;25:339-48; Vasen HF et al. Int. J. Cancer, 2000 Sep;87:809-11; Goldstein AM. Hum. Mutat., 2004 Jun;23:630; Goldstein AM et al. J. Med. Genet., 2007 Feb;44:99-106; Harinck F et al. J. Med. Genet., 2012 Jun;49:362-5). Of note, this alteration is also designated as “p16-Leiden-mutation” in published literature, and has been described as a Dutch founder mutation. Functional analysis of this alteration revealed that transfected cells show altered subcellular localization, and significantly reduced binding affinity to CDK4 relative to wild type cells (McKenzie HA et al. Hum. Mutat. 2010 Jun;31:692-701). The relative risk for pancreatic cancer associated with this specific alteration ranges from 17% (95% CI 3–30) to 47.8% (95% CI 28.4-74.7) (Vasen HF et al. Int. J. Cancer, 2000 Sep;87:809-11; de Snoo FA et al. Clin. Cancer Res. 2008 Nov;14:7151-7). Another study also found that smoking significantly increases risks of various cancers in carriers of this mutation (Potjer TP et al. Eur. J. Hum. Genet. 2015 May;23:711-4). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000493242	SCV000689593	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 19 nucleotides in exon 2 of the CDKN2A gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
MGZ Medical Genetics Center	RCV002288679	SCV002581515	pathogenic	Melanoma-pancreatic cancer syndrome	2022-04-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474829	SCV004212536	pathogenic	Melanoma and neural system tumor syndrome	2021-04-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895073	SCV004716731	pathogenic	CDKN2A-related disorder	2024-02-23	criteria provided, single submitter	clinical testing	The CDKN2A c.225_243del19 variant is predicted to result in a frameshift and premature protein termination (p.Ala76Cysfs*64). It is also known as p16-Leiden, and reported as a Dutch founder variant. This variant has been reported in individuals with melanoma, and cancers of the pancreas and breast (Gruis et al. 1995. PubMed ID: 7640518; Koorstra et al. 2008. PubMed ID: 18813118; Li et al. 2018. PubMed ID: 29316957; Yurgelun et al. 2019. PubMed ID: 29961768). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org) and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/182411/). Frameshift variants in CDKN2A are expected to be pathogenic. This variant is interpreted as pathogenic.