ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.405G>A (p.Gly135=) (rs751586391)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000438522 SCV000523481 likely benign not specified 2017-01-18 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 RCV000474868 SCV000557469 benign Hereditary melanoma 2020-12-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571462 SCV000669158 likely benign Hereditary cancer-predisposing syndrome 2016-02-18 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign
Color Health, Inc RCV000571462 SCV000684532 likely benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000438522 SCV000919122 benign not specified 2019-01-29 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.405G>A alters a non-conserved nucleotide resulting in a synonymous change. 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 8.1e-05 in 272432 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0011 in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Moreover, the variant was also reported in Japanese healthy controls with a frequency of 0.0108 that is approximately 36-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 East Asian/Japanese origin (HGVD). The variant, c.405G>A, has been reported in the literature in individuals from the Japanese population, who were affected with different types of cancer, however without evidence supporting causality (Igaki_1995, Ohnishi_1995, Morita_1998, Takahira_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000438522 SCV001470492 benign not specified 2020-01-28 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000571462 SCV000787996 likely benign Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing

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