ClinVar Miner

Submissions for variant NM_004064.5(CDKN1B):c.281C>T (p.Pro94Leu)

gnomAD frequency: 0.00011  dbSNP: rs757917082
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547203 SCV000646209 uncertain significance Multiple endocrine neoplasia type 4 2023-12-29 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 94 of the CDKN1B protein (p.Pro94Leu). This variant is present in population databases (rs757917082, gnomAD 0.03%). This missense change has been observed in individual(s) with primary hyperparathyroidism (PMID: 32386678). ClinVar contains an entry for this variant (Variation ID: 469015). 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 RCV001016681 SCV001177662 benign Hereditary cancer-predisposing syndrome 2022-06-20 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 RCV001016681 SCV002535480 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-23 criteria provided, single submitter curation
GeneDx RCV002286756 SCV002577099 uncertain significance not provided 2022-03-30 criteria provided, single submitter clinical testing Observed in a patient with MEN4 presenting with hyperprolactinemia without evidence of pituitary adenoma, primary hyperparathyroidism, and parathyroid adenoma (Chevalier et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32386678)
PreventionGenetics, part of Exact Sciences RCV003419969 SCV004116940 uncertain significance CDKN1B-related disorder 2023-09-08 criteria provided, single submitter clinical testing The CDKN1B c.281C>T variant is predicted to result in the amino acid substitution p.Pro94Leu. This variant has been reported in an individual with a complex personal cancer history that included prolactinemia, primary hyperparathyroidism associated with osteoporosis, parathyroid adenoma, breast cancer, ovarian serous cystadenoma, and multifocal micropapillary thyroid carcinoma (Chevalier et al. 2020. PubMed ID: 32386678). It has also been reported in an individual with hairy cell leukemia (Table 1, Dietrich et al. 2015. PubMed ID: 26065650). This variant is reported in 0.029% of alleles in individuals of African descent in gnomAD ( It has conflicting interpretations of benign and uncertain significance in ClinVar ( At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002286756 SCV004220751 uncertain significance not provided 2023-06-04 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with multiple endocrine neoplasia type 4 (MEN4) (PMID: 32386678 (2020)) and hairy cell leukemia (PMID: 26065650 (2015), 8801450 (2017)). The frequency of this variant in the general population, 0.00029 (7/24372 chromosomes in African/African American subpopulation (Genome Aggregation Database,, is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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