ClinVar Miner

Submissions for variant NM_004064.5(CDKN1B):c.125C>T (p.Thr42Ile)

gnomAD frequency: 0.00009  dbSNP: rs200422211
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463157 SCV000541776 uncertain significance Multiple endocrine neoplasia type 4 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 42 of the CDKN1B protein (p.Thr42Ile). This variant is present in population databases (rs200422211, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CDKN1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 404278). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 RCV001010623 SCV001170848 benign Hereditary cancer-predisposing syndrome 2023-06-15 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Sema4, Sema4 RCV001010623 SCV002535469 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-24 criteria provided, single submitter curation
GeneDx RCV002461185 SCV002757231 uncertain significance not provided 2022-11-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26603463, 30065701, 22722193)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000463157 SCV004171506 uncertain significance Multiple endocrine neoplasia type 4 2023-10-20 criteria provided, single submitter clinical testing The CDKN1B c.125C>T (p.Thr42Ile) missense change has a maximum subpopulation frequency of 0.029% in gnomAD v2.1.1 ( The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type 4. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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