ClinVar

Description

Variant summary: CDKN2A c.298G>T (p.Ala100Ser) results in a conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.7e-05 in 236362 control chromosomes, predominantly at a frequency of 0.0013 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-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 or African-American origin. c.298G>T has been reported in the literature without strong evidence for causality (e.g. Yarbrough_1996, Gamieldien_1998, Klangby_1998, Yanagawa_2002, Agrawal_2009, Patel_2017, Shindo_2017, McWilliams_2018). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Experimental evidence indicated that the variant does not significantly affect protein function (Lindstrom_2001, Miller_2011, Ng_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant with as benign (n=2), likely benign (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as benign.