ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.151-4G>C (rs529380972)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130188 SCV000185025 uncertain significance Hereditary cancer-predisposing syndrome 2014-03-05 criteria provided, single submitter clinical testing The c.194-4G>C intronic variant (also known as c.151-4G>C) results from a G to C substitution 4 nucleotides upstream from coding exon 2 in the CDKN2A gene. This alteration has been described in an individual diagnosed with early-onset hepatic carcinoma but hasn't been reported in melanoma cohorts to date (Chaubert P et al. Hepatology 1997; 25:1376-81). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This nucleotide position is not well conserved in available vertebrate species. To date, this alteration has been detected with an allele frequency of approximately 0.16% (greater than 600 alleles tested) in our clinical cohort (includes this individual). Based on nucleotide sequence alignment, this position is well conserved in available vertebrate species.Using the BDGP and ESEfinder splice site prediction tools, this alteration does not have any significant effect on the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.676-5T>C remains unclear.
Counsyl RCV000410358 SCV000489089 likely benign Melanoma-pancreatic cancer syndrome 2016-08-16 criteria provided, single submitter clinical testing
GeneDx RCV000431130 SCV000517091 benign not specified 2017-01-10 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000467989 SCV000557471 benign Hereditary melanoma 2020-12-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000431130 SCV000601017 benign not specified 2017-05-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130188 SCV000689586 benign Hereditary cancer-predisposing syndrome 2016-06-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000585904 SCV000695334 benign not provided 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The CDKN2A c.151-4G>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. One functional study found that this variant does not affect splicing (Loo_Oncogene_2003). The variant of interest has been found in a large, broad control population, ExAC in 224/82416 control chromosomes (2 homozygotes) at a frequency of 0.0027179, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic CDKN2A variant (0.0003), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases recently classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Broad Institute Rare Disease Group, Broad Institute RCV001258294 SCV001435228 benign Hepatocellular carcinoma criteria provided, single submitter research The heterozygous c.151-4G>C variant in CDKN2A has been identified in an individual with hepatocellular carcinoma (PMID: 9185756), but has also been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC ( In summary, this variant meets criteria to be classified as benign for autosomal dominant hepatocellular carcinoma.

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