12-12718195-T-C

Variant names:

• chr12-12718195-T-C
• rs142833529
• NM_004064.5:c.356T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004064.5(CDKN1B):​c.356T>C​(p.Ile119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000706 in 1,613,028 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I119S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (2 hom.)
• Consequence: CDKN1B NM_004064.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:9
• Conservation: PhyloP100: 0.482
• Publications: 23 publications found

Genes affected

CDKN1B (HGNC:1785): (cyclin dependent kinase inhibitor 1B) This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. Mutations in this gene are associated with multiple endocrine neoplasia type IV (MEN4). [provided by RefSeq, Apr 2014]

CDKN1B Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
• multiple endocrine neoplasia

  Inheritance: AD Classification: STRONG Submitted by: G2P
• hereditary nonpolyposis colon cancer

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01424861).
• BP6: Variant 12-12718195-T-C is Benign according to our data. Variant chr12-12718195-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 307664.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000611 (93/152294) while in subpopulation AMR AF = 0.00118 (18/15300). AF 95% confidence interval is 0.00076. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1B	NM_004064.5	c.356T>C	p.Ile119Thr	missense_variant	Exon 1 of 3	ENST00000228872.9	NP_004055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1B	ENST00000228872.9	c.356T>C	p.Ile119Thr	missense_variant	Exon 1 of 3	1	NM_004064.5	ENSP00000228872.4

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000533 AC: 132 AN: 247708 AF XY: 0.000512

Gnomad AFR exome AF: 0.0000659

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.000760

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000715 AC: 1045 AN: 1460734 Hom.: 2 Cov.: 39 AF XY: 0.000681 AC XY: 495 AN XY: 726670

African (AFR) AF: 0.0000899 AC: 3 AN: 33388

American (AMR) AF: 0.00112 AC: 50 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.000171 AC: 9 AN: 52730

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.000839 AC: 933 AN: 1111772

Other (OTH) AF: 0.000679 AC: 41 AN: 60368

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74474

African (AFR) AF: 0.000265 AC: 11 AN: 41562

American (AMR) AF: 0.00118 AC: 18 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000748 Hom.: 0

Bravo AF: 0.000812

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000453 AC: 55

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia type 4 Uncertain:2 Benign:3

Nov 06, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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.

Aug 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN1B c.356T>C; p.Ile119Thr variant (rs142833529, ClinVar Variation ID: 307664) is reported in the literature in multiple individuals affected with CDKN1B-related conditions, including myeloproliferative disorder, premature ovarian failure, pituitary adenoma, and Cushing's Disease (Chang 2004, Chasseloup 2020, Lavezzi 2022, Martinez de LaPiscina 2021, Ojeda 2011, Pappa 2005, Rasouly 2019, Tichomirowa 2012). This variant is found in the Admixed American population with an allele frequency of 0.11% (39/ 35308 alleles) in the Genome Aggregation Database (v2.1.1), and has been identified in control cohorts and unaffected relatives of affected probands (Tichomirowa 2012 and Chang 2004). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.32), though functional studies indicate elevated resistance to proteasomal degradation compared to wild type (Tichomirowa 2012). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Chang BL et al. A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer. Cancer Res. 2004 Mar 15;64(6):1997-9. PMID: 15026335. Chasseloup F et al. Germline CDKN1B Loss-of-Function Variants Cause Pediatric Cushing's Disease With or Without an MEN4 Phenotype. J Clin Endocrinol Metab. 2020 Jun 1;105(6):1983–2005. PMID: 32232325 Lavezzi E et al. Case Report: New CDKN1B Mutation in Multiple Endocrine Neoplasia Type 4 and Brief Literature Review on Clinical Management. Front Endocrinol (Lausanne). 2022 Mar 9;13:773143. PMID: 35355569 Martinez de LaPiscina I et al. Clinical and genetic characteristics in patients under 30 years with sporadic pituitary adenomas. Eur J Endocrinol. 2021 Aug 27;185(4):485-496. PMID: 34313605. Ojeda D et al. Sequence analysis of the CDKN1B gene in patients with premature ovarian failure reveals a novel mutation potentially related to the phenotype. Fertil Steril. 2011 Jun 30;95(8):2658-60.e1. PMID: 21575944. Pappa V et al. A novel p27 gene mutation in a case of unclassified myeloproliferative disorder. Leuk Res. 2005 Feb;29(2):229-31. PMID: 15607373. Rasouly HM et al. The Burden of Candidate Pathogenic Variants for Kidney and Genitourinary Disorders Emerging From Exome Sequencing. Ann Intern Med. 2019 Jan 1;170(1):11-21. PMID: 30476936. Tichomirowa MA et al. Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. Endocr Relat Cancer. 2012 May 3;19(3):233-41. PMID: 22291433.

Nov 08, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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]

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1 Benign:3

Dec 23, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKN1B: BP4, BS1:Supporting

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: 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.

Apr 11, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with pituitary adenoma, neuroendocrine tumor, prostate cancer, and/or premature ovarian failure, but was also observed in unaffected controls (PMID: 15026335, 21575944, 22291433, 32232325, 35355569, 34313605); Published functional studies demonstrate expression and cellular localization similar to wild type, but also proteasome degradation resistance, increased protein stability, slightly delayed migration, and reduced RHOA and CDK2 interaction (PMID: 22291433, 32232325); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28824003, Hernndez-Ramrez_2019, 30990521, 24101221, 15607373, 21575944, 34426522, 15026335, 22291433, 34313605, Zuarth-Vazquez2023[abstract], 35355569, 32232325, 30065701, 36520683, 36149413, 30476936)

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Mar 03, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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.

Aug 05, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.356T>C, located in exon 1 of the CDKN1B gene, is predicted to result in the substitution of isoleucine with threonine at codon 119, p.(Ile119Thr). This variant is found in 143/265372 alleles at a frequency of 0.054% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score (0.32) for this variant is indeterminate regarding the effect that it may have on protein function according Pejaver 2022 thresholds (PMID: 36413997). To our knowledge, no well-established functional studies have been reported for this variant. CDKN1B c.356T>C was identified in our clinical cohort of patients in one patient affected with a neuroendocrine tumor as well as in several patients affected with breast cancer, colorrectal or pancreatic cancer among others. This variant has been reported in the ClinVar database (1x benign, 8x likely benign, 3x uncertain significance) and in the LOVD database (2x likely benign, 1x uncertain significance). Based on the currently available evidence, c.356T>C is classified as an uncertain significance variant according to ACMG guidelines.

Jul 05, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

not specified Uncertain:1

Oct 06, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

CDKN1B-related disorder Benign:1

Mar 16, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: 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).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.78
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		0.48
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.17	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.23	T;T
Sift4G	Benign	0.62	T;T
Vest4		0.040
ClinPred		0.0055	T
GERP RS		1.3
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.23
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142833529; hg19: chr12-12871129; COSMIC: COSV104563832;