ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.170C>T (p.Ala57Val) (rs372266620)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079843 SCV000261199 likely benign Hereditary melanoma 2020-12-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000215562 SCV000274603 likely benign Hereditary cancer-predisposing syndrome 2018-05-02 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
GeneDx RCV000587917 SCV000292536 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.170C>T at the cDNA level, p.Ala57Val (A57V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). CDKN2A Ala57Val has been identified in individuals with melanoma, including at least one patient that also had pancreatic cancer (Soufir 1998, Soufir 2004, Begg 2005, Orlow 2007, Kannengiesser 2009, Spica 2011), but was also observed at equal frequencies in cases (4/703) and controls (4/691) in a melanoma case-control study (Goldstein 2008). On functional interrogation, CDKN2A Ala57Val was able to partially bind CDK4 and resulted in elevated levels of reactive oxygen species (Jenkins 2013, Kannengiesser 2009). CDKN2A Ala57Val was observed at an allele frequency of 0.013% (2/15,950) in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant is located in the ANK 2 repeat domain (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDKN2A Ala57Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587917 SCV000601019 uncertain significance not provided 2019-03-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587917 SCV000695335 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The CDKN2A c.170C>T (p.Ala57Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). CDKN2A Ala57 is not conserved across species and is located within the second of four ANK repeats of the p16 protein (Jenkins 2013) which is at the beginning of the a helix (Figure 1), in close contact with conserved hydrogen-bond networks that have a central role in CDK6 binding (Russo et al, 1998). Although Ala57 is not a conserved amino acid across species, its proximity to the alpha helix of the second ankyrin repeat may place spatial constraints that may be altered with a valine substitution. A57V occurs in the overlapping coding sequence of p14ARF, however, it result in a synonymous p14ARF variant, designated R112R.Several functional studies have been published on CDKN2A Ala57Val. Experimental studies have shown that this missense change can partially bind CDK4, resulted in elevated levels of reactive oxygen species, but retained the cell cycle arrest function (Jenkins 2013, Kannengiesser 2009). The clinical significance of elevated levels of reactive oxygen species (ROS) compared to wild-type p16 is unknown. A subsequent study which applied a computational methodology combining functional data from a cell cycle assay, as well as epidemiological and prediction data, classified this variant as having uncertain significance (Miller 2011). As all published studies at the time of classification examined only the effects of the A57V variant at the protein level, it is possible that c.170C>T might influence the transcription, splicing, processing, or translation of p16 RNA or p14 RNA in ways that are not discernible by ectopic expression of the cloned cDNA.CDKN2A Ala57Val has been identified multiple melanoma patients, one of whom also had pancreatic cancer, and also in one acute lymphoblastic leukaemia patient. This variant was found in 13/106106 control chromosomes at a frequency of 0.0001225, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDKN2A variant (0.0003). However, the variant was also observed at equal frequencies in cases (4/703) and controls (4/691) in a melanoma case-control study (Goldstein 2008). Furthermore, in one affected family it did not segregate with the disease (Kannengiesser 2009). In addition, multiple clinical diagnostic laboratories classified this variant as a VUS and one as Likely Benign. In summary, this is a rare missense change that has been found at similar frequencies in affected and unaffected individuals. It did not segregate with disease in one family and has been shown to have only a mild impact on protein function. For these reasons, this variant has been classified as a VUS-possibly benign until additional co-segregation data is available.
PreventionGenetics,PreventionGenetics RCV000587917 SCV000805822 uncertain significance not provided 2017-01-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000215562 SCV000910726 benign Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing
Mendelics RCV000988157 SCV001137774 benign Melanoma-pancreatic cancer syndrome 2019-05-28 criteria provided, single submitter clinical testing

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