ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.320G>A (p.Arg107His) (rs370823171)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221998 SCV000273497 likely benign Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000221998 SCV000689602 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
GeneDx RCV000160407 SCV000210940 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.320G>A at the cDNA level, p.Arg107His (R107H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant was observed in one control individual in a melanoma case-control study (Miller 2011). CDKN2A Arg107His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDKN2A Arg107His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780105 SCV000917147 uncertain significance not specified 2018-07-09 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.320G>A (p.Arg107His) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 232676 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.320G>A in individuals affected with Cutaneous Malignant Melanoma and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, 3 of whom have classified this variant as uncertain significance, while one has classified it as likely benign based upon co-occurrence with an unspecified mutation in another gene that clearly explains a proband's phenotype. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000464667 SCV000545549 uncertain significance Hereditary cutaneous melanoma 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 107 of the CDKN2A (p16INK4a) protein (p.Arg107His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs370823171, ExAC 0.002%). This variant has been reported in an individual affected with acute lymphoblastic leukemia (PMID: 26104880). ClinVar contains an entry for this variant (Variation ID: 182413). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The histidine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.