ClinVar Miner

Submissions for variant NM_004064.4(CDKN1B):c.407A>G (p.Asp136Gly) (rs546234840)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000475865 SCV000377018 benign Multiple endocrine neoplasia, type 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000475865 SCV000541772 uncertain significance Multiple endocrine neoplasia, type 4 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 136 of the CDKN1B protein (p.Asp136Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs546234840, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CDKN1B-related disease. ClinVar contains an entry for this variant (Variation ID: 307666). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
Ambry Genetics RCV001021820 SCV001183485 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-09 criteria provided, single submitter clinical testing Insufficient evidence

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