ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.384G>A (p.Arg128=) (rs199901898)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163455 SCV000214003 likely benign Hereditary cancer-predisposing syndrome 2014-10-13 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV001080226 SCV000254242 likely benign Hereditary melanoma 2020-12-06 criteria provided, single submitter clinical testing
Counsyl RCV000410792 SCV000489450 likely benign Melanoma-pancreatic cancer syndrome 2016-10-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163455 SCV000684528 likely benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759024 SCV000888057 benign not provided 2017-11-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781221 SCV000919124 benign not specified 2019-04-01 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.384G>A alters a non-conserved nucleotide resulting in a synonymous change. 3/5 computational tools predict the variant weakens a potential cryptic 5' donor site located within the exon. However, this is not expected to significantly impact splicing and these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 272620 control chromosomes, predominantly at a frequency of 0.00038 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately equal to 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 Latino origin. c.384G>A has been reported in the literature in affected individuals (Orlow_2007, Landi_2004). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. A co-occurrence with a pathogenic variant has been reported in our internal database (BRCA2 c.5576_5579delTTAA, p.I1859fs*3), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (1x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000410792 SCV001137757 likely benign Melanoma-pancreatic cancer syndrome 2019-05-28 criteria provided, single submitter clinical testing

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