Submissions for variant NM_000077.5(CDKN2A):c.151-1G>C

dbSNP: rs730881677

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254654	SCV000210945	pathogenic	not provided	2016-08-20	criteria provided, single submitter	clinical testing	The c.151-1 G>C splice site variant in the CDKN2A gene destroys the canonical splice acceptor site in intron 1, and appears to cause aberrant splicing of both the p16(INK4a) and p14(ARF) transcripts leading to severely abnormal proteins (Prowse et al., 2003). In the family reported by Prowse et al., several confirmed CDKN2A variant carriers were reported to have multiple benign and malignant tumors including melanoma, neurofibromas, an osteochondroma, and early-onset breast cancer (although the relationship of the variant to the increased risk of breast cancer in the reported family is unknown).
Ambry Genetics	RCV000160412	SCV000277276	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-26	criteria provided, single submitter	clinical testing	The c.151-1G>C intronic pathogenic mutation results from a G to C one nucleotide upstream from coding exon 2 of the CDKN2A gene. This variant has been observed in patients with personal and family histories of melanoma and/or other tumors such as neurofibromas and peripheral nerve sheath tumors (Petronzelli F et al. Genes Chromosomes Cancer 2001 Aug; 31(4):398-401; Sargen MR et al. Br. J. Dermatol. 2016 Oct;175(4):785-9; Hocevar M et al. Croat. Med. J. 2006 Dec;47(6):851-4; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have shown that this variant results in aberrant splicing (Petronzelli F et al. Genes Chromosomes Cancer 2001 Aug; 31(4):398-401; Prowse AH et al. J. Med. Genet. 2003 Aug; 40(8):e102). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850264	SCV002158387	pathogenic	Familial melanoma	2023-10-09	criteria provided, single submitter	clinical testing	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 affects an acceptor splice site in intron 1 of the CDKN2A (p16INK4a) gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of melanoma-NST syndrome (PMID: 11433531, 12920094, 26876133). It has also been observed to segregate with disease in related individuals. This variant is also known as c.194-1G>C in CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 182416). Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 11433531, 12920094). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. The evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a) and CDKN2A (p14ARF)-associated conditions.