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

gnomAD frequency: 0.00011  dbSNP: rs757917082

Total submissions: 6

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 (http://gnomad.broadinstitute.org/variant/12-12871054-C-T). It has conflicting interpretations of benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/469015/). 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, http://gnomad.broadinstitute.org)), 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.