ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.266G>A (p.Gly89Asp) (rs137854599)

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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 RCV000219725 SCV000275864 likely pathogenic Hereditary cancer-predisposing syndrome 2017-08-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Significant disease association in appropriately sized case-control study(ies),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Color RCV000219725 SCV000906449 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-12 criteria provided, single submitter clinical testing
GeneDx RCV000493646 SCV000582103 pathogenic not provided 2018-02-02 criteria provided, single submitter clinical testing The G89D variant in the CDKN2A gene has been reported as a highly penetrant risk allele which isstrongly associated with increased melanoma risk, and is theorized to be an Icelandic pathogenicfounder variant (Goldstein et al., 2008). The G89D variant was not observed in approximately 6,400individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. This substitution occurs at aposition that is not conserved. However, this position is within the ANK 3 repeat domain (Uniprot).The G89D variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties, and in silicoanalysis predicts this variant is probably damaging to the protein structure/function. Multiple missensevariants in nearby residues have been reported in the Human Gene Mutation Database in associationwith CDKN2A-related disorders (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Based on the currently available evidence, we consider G89D to be pathogenic.
Invitae RCV000122946 SCV000166204 uncertain significance Hereditary cutaneous melanoma 2017-06-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 89 of the p16INK4a protein (p.Gly89Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This sequence change has been reported as a suspected founder mutation associated with increased risk for melanoma, head and neck cancers, and pancreatic carcinoma in the Icelandic population (PMID: 18178632). However, the reported risk does not meet statistical significance when corrected for multiple hypothesis testing (Bonferroni correction). Furthermore, the significance of this variant in individuals of non-Icelandic descent is uncertain. ClinVar contains an entry for this variant (Variation ID: 9426). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. It has been hypothesized to be an increased risk allele in the Icelandic population, but the available study is currently insufficient to support this assertion with statistical significance. For these reasons, this change has been classified as a Variant of Uncertain Significance.
OMIM RCV000010033 SCV000030254 risk factor Cutaneous malignant melanoma 2 2017-08-17 no assertion criteria provided literature only

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