Submissions for variant NM_000077.5(CDKN2A):c.358del (p.Glu120fs)

dbSNP: rs1060501263

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465157	SCV000545532	pathogenic	Familial melanoma	2022-06-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val126 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7647780, 7987387, 8668202, 10389768, 11595726, 23371019). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 406710). This premature translational stop signal has been observed in individual(s) with melanoma and other cancer types (PMID: 539244, 9439668, 10874641, 25780468, 26681309). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu120Serfs*26) in the CDKN2A (p16INK4a) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the CDKN2A (p16INK4a) protein.
Color Diagnostics, LLC DBA Color Health	RCV000775814	SCV000910275	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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.
Ambry Genetics	RCV000775814	SCV002615229	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	The c.358delG pathogenic mutation, located in coding exon 2 of the CDKN2A gene, results from a deletion of one nucleotide at nucleotide position 358, causing a translational frameshift with a predicted alternate stop codon (p.E120Sfs*26). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of CDKN2A, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 37 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. However, this alteration has been identified in multiple Spanish patients and families with cutaneous malignant melanoma and was shown to segregate with disease in four individuals in a family (Puig S et al. Hum. Genet., 1997 Dec;101:359-64; De Unamuno B et al. Melanoma Res., 2018 06;28:246-249; de Torre C et al. Exp. Dermatol., 2010 Aug;19:e333-5). In addition, this variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.