Submissions for variant NM_000077.5(CDKN2A):c.457+1_457+10del

dbSNP: rs1587330284

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001022717	SCV001184485	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-10	criteria provided, single submitter	clinical testing	The c.457+1_457+10del10 intronic variant, located in intron 2 of the CDKN2A gene, results from a deletion of 10 nucleotides at positions c.457+1 to c.457+10. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049532	SCV001213586	uncertain significance	Familial melanoma	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 2 of the CDKN2A (p16INK4a) gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 825010). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV003153890	SCV003842611	likely pathogenic	not provided	2022-09-20	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003473596	SCV004212525	likely pathogenic	Melanoma and neural system tumor syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001049532	SCV005040211	likely pathogenic	Familial melanoma	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.457+1_457+10del10 is located in a canonical splice-site in the penultimate exon and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. These predictions have yet to be confirmed by functional studies. However, skipping of exon 2 has been observed as a mechanism of disease for at least one CDKN2A variant located in the last nucleotide of exon 2, namely c.457G>T (p.Asp153Tyr) (Variation ID: 216035), supporting the functional relevance of the downstream region for protein function. The variant was absent in 245936 control chromosomes. To our knowledge, no occurrence of c.457+1_457+10del10 in individuals affected with Cutaneous Malignant Melanoma and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 825010). Based on the evidence outlined above, the variant was classified as likely pathogenic.