ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.298G>T (p.Ala100Ser) (rs200863613)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588034 SCV000149242 uncertain significance not provided 2018-10-19 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.298G>T at the cDNA level, p.Ala100Ser (A100S) at the protein level, and results in the change of an Alanine to a Serine (GCC>TCC). This variant was observed in an individual with a personal history suggestive of Multiple Endocrine Neoplasia type 1 (Agarwal 2009) as well as a familial melanoma kindred (Yarbrough 1996, Yarbrough 2002). Of note, the kindred reported by Yarbrough et al. was also found to harbor an in-frame CDKN2A deletion encompassing residues 96-99 and thought to be responsible for the disease in this family. In vitro functional studies of CDKN2A Ala100Ser demonstrated cell cycle arrest activity, protein expression, and protein binding comparable to wildtype (Agarwal 2009, Miller 2011). However, Miller et al. (2011) deemed the results of the cell cycle arrest activity analysis unreliable due to the associated large standard deviation for error. CDKN2A Ala100Ser was observed with an allele frequency of 0.1% (26/22,878) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the third ANK repeat (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDKN2A Ala100Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000229571 SCV000283442 likely benign Hereditary melanoma 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000570355 SCV000669175 likely benign Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
Color Health, Inc RCV000570355 SCV000689600 benign Hereditary cancer-predisposing syndrome 2021-01-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855587 SCV000695338 likely benign not specified 2020-10-05 criteria provided, single submitter clinical testing 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). Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign while three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000988151 SCV001137764 uncertain significance Melanoma-pancreatic cancer syndrome 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000855587 SCV001470488 benign not specified 2020-07-30 criteria provided, single submitter clinical testing

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