Submissions for variant NM_004064.5(CDKN1B):c.407A>G (p.Asp136Gly)

gnomAD frequency: 0.00020  dbSNP: rs546234840

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475865	SCV000541772	likely benign	Multiple endocrine neoplasia type 4	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001021820	SCV001183485	benign	Hereditary cancer-predisposing syndrome	2022-12-01	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.
GeneDx	RCV001357065	SCV001982319	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	Identified in a patient with Cushing's disease and in a patient with pancreatic cancer (PMID: 32232325, 32923899); Published functional studies are inconclusive: displayed normal subcellular localization and hormonal production, but decreased protein stability and interaction with RHOA and CDK2 (PMID: 32232325); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32232325, 32923899, 35355569, 36520683, 36149413)
Sema4, Sema4	RCV001021820	SCV002535491	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-20	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001357065	SCV004220758	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00013 (16/127796 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in at least one individual with Cushing's disease (PMID: 32232325 (2020) and 36149413 (2022)). A published functional study has also shown that this variant has a partial effect on CDKN1B protein function (PMID: 32232325 (2020)). However, 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.
CeGaT Center for Human Genetics Tuebingen	RCV001357065	SCV004700945	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CDKN1B: BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357065	SCV001552399	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CDKN1B p.Asp136Gly variant was identified in 1 of 406 proband chromosomes (frequency: 0.0025) from individuals or families with Multiple Endocrine Neoplasia type 4 (Hernandez-Ramirez_2019). The variant was identified in dbSNP (ID: rs546234840), ClinVar (classified as likely benign by Illumina and as a VUS by Invitae for Multiple Endocrine Neoplasia) and Cosmic (FATHMM prediction: pathogenic; score=0.9). The variant was also identified in control databases in 21 of 278260 chromosomes at a frequency of 0.000075 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 7148 chromosomes (freq: 0.00014), European (non-Finnish) in 16 of 127796 chromosomes (freq: 0.000125) and Latino in 4 of 35340 chromosomes (freq: 0.000113); it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The p.Asp136 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003409475	SCV004113079	uncertain significance	CDKN1B-related disorder	2024-03-07	no assertion criteria provided	clinical testing	The CDKN1B c.407A>G variant is predicted to result in the amino acid substitution p.Asp136Gly. This variant was reported in an individual with Cushing disease and was classified as uncertain (Chasseloup et al. 2020. PubMed ID: 32232325). Functional studies found this variant may impact protein function (Chasseloup et al. 2020. PubMed ID: 32232325). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is listed in ClinVar as uncertain and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/307666/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.