ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.273G>A (p.Leu91=) (rs4987127)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570074 SCV000669172 likely benign Hereditary cancer-predisposing syndrome 2015-05-06 criteria provided, single submitter clinical testing
Color RCV000570074 SCV000910849 likely benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Counsyl RCV000411786 SCV000488927 likely benign Melanoma-pancreatic cancer syndrome 2016-07-19 criteria provided, single submitter clinical testing
GeneDx RCV000656828 SCV000292538 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.316G>A at the cDNA level, p.Gly106Arg (G106R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA) in exon 2 of the p14-ARF protein. The CDKN2A gene encodes the p16 protein and, using an alternate reading frame, the p14-ARF protein as well. Of note, this variant also results in a change to the p16 protein; however, that amino acid substitution is silent (p.Leu91Leu). CDKN2A Gly106Arg was observed in an individual with melanoma and their unaffected family member, however additional variants were detected in the affected individual as well as in another affected family member who did not carry the CDKN2A Gly106Arg variant (Mangas 2016). This variant was identified in 1/46 healthy African-European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. Additionally, CDKN2A Gly106Arg was observed at an allele frequency of 0.1% (25/22,918) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDKN2A Gly106Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120545 SCV000084699 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000120545 SCV000917152 benign not specified 2018-12-14 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.273G>A alters a conserved nucleotide resulting in a synonymous change. One of two in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 262192 control chromosomes, predominantly at a frequency of 0.0011 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 3.67 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.273G>A has been reported in the literature. These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000226789 SCV000283441 likely benign Hereditary cutaneous melanoma 2016-11-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120545 SCV000601022 likely benign not specified 2017-03-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656828 SCV000888051 likely benign not provided 2017-03-22 criteria provided, single submitter clinical testing

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