ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570355 SCV000669175 likely benign Hereditary cancer-predisposing syndrome 2017-10-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Other data supporting benign classification
Color RCV000570355 SCV000689600 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-03 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000588034 SCV000695338 likely benign not provided 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The c.298G>T variant affects a conserved nucleotide, resulting in amino acid change from Ala to Ser. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is found in 16/111090 control chromosomes at a frequency of 0.000144, predominantly observed in African subpopulation in ExAC with MAF of 0.00193. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0003), indicating this variant is likely a benign polymorphism. This variant has been detected in case with multiple endocrine neoplasia type 1 and the authors classified this variant as benign (Agrawal_2009). This variant is located outside of the CDK4 interacting segment (Baumgartner_1998) and functional studies showed that this variant does not affect p14ARF's nucleolar localization or ability to induce p53 (Lindstrom_2001) and this variant showed comparable cell cycle arrest function as WT p16ING4a (Miller_2011) . One clinical laboratory/reputable database classified this variant as vus, without evidence to independently evaluate. Talen together, the variant was classified as likely benign until additional information becomes available.
Invitae RCV000229571 SCV000283442 likely benign Hereditary cutaneous melanoma 2017-12-27 criteria provided, single submitter clinical testing

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