ClinVar Miner

Submissions for variant NM_004064.5(CDKN1B):c.356T>C (p.Ile119Thr)

gnomAD frequency: 0.00057  dbSNP: rs142833529
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000457158 SCV000377015 likely benign Multiple endocrine neoplasia type 4 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000457158 SCV000541764 likely benign Multiple endocrine neoplasia type 4 2024-01-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563714 SCV000673204 benign Hereditary cancer-predisposing syndrome 2022-03-03 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.
Baylor Genetics RCV000457158 SCV001483044 uncertain significance Multiple endocrine neoplasia type 4 2018-11-08 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 15607373, 21575944, 22291433]
Genetic Services Laboratory, University of Chicago RCV001820909 SCV002071166 uncertain significance not specified 2021-10-06 criteria provided, single submitter clinical testing DNA sequence analysis of the CDKN1B gene demonstrated a sequence change, c.356T>C, in exon 1 that results in an amino acid change, p.Ile119Thr. This sequence change has been described in an individual with myeloproliferative disorder (PMID: 15607373), an individual with Cushing’s disease (PMID: 32232325), an individual with premature ovarian failure (PMID: 21575944), and in an individual with acromegaly (PMID: 22291433). This sequence change is present in the gnomAD database with a frequency of 0.11% in the Latino/Admixed American subpopulation (dbSNP rs142833529). The p.Ile119Thr change affects a moderately conserved amino acid residue located in a domain of the CDKN1B protein that is not known to be functional. The p.Ile119Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). An in vitro assay demonstrated protein instability and disruption of the scatter domain of CDKN1B for this sequence change (PMID: 32232325). Due to insufficient evidences, the clinical significance of the p.Ile119Thr change remains unknown at this time.
Sema4, Sema4 RCV000563714 SCV002535484 likely benign Hereditary cancer-predisposing syndrome 2021-07-05 criteria provided, single submitter curation
GeneDx RCV001355182 SCV002586753 uncertain significance not provided 2023-07-25 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate expression and cell localization similar to wild type, but also proteasome degradation resistance and increased protein stability compared to wild type (Tichomirowa et al., 2012); Observed in individuals with pituitary adenoma, prostate cancer, and premature ovarian failure in published literature, but was also observed in unaffected controls (Chang et al., 2004; Ojeda et al., 2011; Tichomirowa et al., 2012; Martnez de LaPiscina et al., 2021); This variant is associated with the following publications: (PMID: 30065701, 28824003, Hernndez-Ramrez_2019, 30990521, 24101221, 15607373, 21575944, 32232325, 34426522, 15026335, 22291433, 35355569, 34313605, 36520683)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001355182 SCV004220756 likely benign not provided 2022-12-23 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003930302 SCV004737473 likely benign CDKN1B-related disorder 2022-03-16 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355182 SCV001549988 likely benign not provided no assertion criteria provided clinical testing The CDKN1B p.Ile119Thr variant was identified in four individuals with varying phenotypes including prostate cancer, somatotropinoma, premature ovarian failure, and myeloproliferative syndrome (Chang_2004_PMID: 15026335; Tichomirowa_2012_PMID: 22291433; Ojeda_2011_PMID: 21575944; Pappa_2004_PMID: 15607373). Furthermore, this variant was also found in one heterozygous control (Tichomirowa_2012_PMID: 22291433). The variant was identified in dbSNP (ID: rs142833529) and ClinVar (classified as likely benign by Invitae and Illumina, and as uncertain significance by Ambry Genetics). The variant was not identified in the Cosmic database. The variant was identified in control databases in 143 of 265372 chromosomes at a frequency of 0.0005389 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Latino in 39 of 34986 chromosomes (freq: 0.001115), European (non-Finnish) in 94 of 116912 chromosomes (freq: 0.000804), Other in 4 of 6658 chromosomes (freq: 0.000601), European (Finnish) in 3 of 24810 chromosomes (freq: 0.000121), African in 2 of 22624 chromosomes (freq: 0.000088) and East Asian in 1 of 19096 chromosomes (freq: 0.000052), but was not observed in the Ashkenazi Jewish or South Asian populations. The p.Ile119 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.