Submissions for variant NM_000077.5(CDKN2A):c.2T>A (p.Met1Lys)

gnomAD frequency: 0.00001  dbSNP: rs759871071

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567259	SCV000676323	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-24	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.2T>A), located in coding exon 1 of the CDKN2A gene, results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine nine amino acids from the initiation site and the significance of the N-terminus for this protein is not well established. This alteration has been reported in the literature in one individual with non-familial melanoma (Ghiorzo P et al. Exp. Dermatol., 2012 Sep;21:718-20). This amino acid position is not well conserved on limited sequence alignment. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000586260	SCV000681013	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which a downstreamin-frame ATG could serve as an alternate initiator codon; Not observed at significant frequency in large population cohorts (gnomAD); Alternate variant at this site (c.2T>G) has been observed in an individual with cutaneous melanoma (Ghiorzo et al., 2012); This variant is associated with the following publications: (PMID: 36243179, 36988593, 22804906)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586260	SCV000695328	uncertain significance	not provided	2015-11-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638963	SCV000760520	uncertain significance	Familial melanoma	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the CDKN2A (p16INK4a) mRNA. The next in-frame methionine is located at codon 9. This variant is present in population databases (rs759871071, gnomAD 0.003%). 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: 487018). 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.
Color Diagnostics, LLC DBA Color Health	RCV000567259	SCV000910001	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-30	criteria provided, single submitter	clinical testing	This variant alters the translation initiation codon in the CDKN2A (p16INK4A) mRNA. However, another in-frame methionine is located at codon 9, which may be able to rescue translation initiation. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in an individual affected with hereditary cancer, however, another initiation codon variant (c.2T>G) has been observed in an individual with melanoma (PMID: 22804906). This variant has been identified in 3/215390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321685	SCV004027502	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003159969	SCV002758065	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research