NM_004064.5(CDKN1B):c.206C>T (p.Pro69Leu) AND Multiple endocrine neoplasia type 4

Germline classification:: Conflicting classifications of pathogenicity (5 submissions)
Last evaluated:: Jan 11, 2025
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000162207.19

Allele description [Variation Report for NM_004064.5(CDKN1B):c.206C>T (p.Pro69Leu)]

NM_004064.5(CDKN1B):c.206C>T (p.Pro69Leu)

Gene:

CDKN1B:cyclin dependent kinase inhibitor 1B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p13.1

Genomic location:

Preferred name:

NM_004064.5(CDKN1B):c.206C>T (p.Pro69Leu)

HGVS:

NC_000012.12:g.12718045C>T
NG_016341.1:g.5678C>T
NM_004064.5:c.206C>TMANE SELECT
NP_004055.1:p.Pro69Leu
NP_004055.1:p.Pro69Leu
NC_000012.11:g.12870979C>T
NM_004064.3:c.206C>T
NM_004064.4:c.206C>T
P46527:p.Pro69Leu

Protein change:

P69L; PRO69LEU

Links:

UniProtKB: P46527#VAR_064429; OMIM: 600778.0003; dbSNP: rs777354267

NCBI 1000 Genomes Browser:

rs777354267

Molecular consequence:

NM_004064.5:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Multiple endocrine neoplasia type 4
Synonyms:: MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV
Identifiers:: MONDO: MONDO:0012552; MedGen: C1970712; OMIM: 610755

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000212164	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2010)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001395064	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 11, 2025)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29625052, 32386678, 20824794, 28492532
SCV003823115	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 19, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005045519	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 27, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005416189	Juno Genomics, Hangzhou Juno Genomics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Pathogenic Germline Variants in 10,389 Adult Cancers.

Huang KL, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, Paczkowska M, Reynolds S, Wyczalkowski MA, Oak N, Scott AD, Krassowski M, Cherniack AD, Houlahan KE, Jayasinghe R, Wang LB, Zhou DC, Liu D, Cao S, Kim YW, Koire A, McMichael JF, et al.

Cell. 2018 Apr 5;173(2):355-370.e14. doi: 10.1016/j.cell.2018.03.039.

PubMed [citation]

PMID:: 29625052
PMCID:: PMC5949147

Multiple Endocrine Neoplasia Type 4: Novel CDNK1B variant and immune anomalies.

Chevalier B, Odou MF, Demonchy J, Cardot-Bauters C, Vantyghem MC.

Ann Endocrinol (Paris). 2020 Jun;81(2-3):124-125. doi: 10.1016/j.ando.2020.04.002. Epub 2020 Apr 10. No abstract available.

PubMed [citation]

PMID:: 32386678

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000212164.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 79-year-old Caucasian woman with multiple endocrine neoplasia type IV (MEN4; 610755), Molatore et al. (2010) identified a heterozygous c.678C-T transition in the CDKN1B gene, resulting in a pro69-to-leu (P69L) substitution. The mutation, which was found by direct sequencing, was not present in the dbSNP database or in 370 control individuals. In vitro cellular expression studies showed that the mutation caused reduced mutant protein levels due to more rapid degradation, as well as slightly higher cytoplasmic localization compared to wildtype. Molecular modeling indicated that the mutation affected a CDK2 (116953)-binding site, and immunoblot analysis confirmed that the mutant protein could not bind CDK2. The P69L mutant protein was less effective at suppressing growth of neuroendocrine tumor cells in vitro compared to wildtype. The patient had bronchial carcinoid, a nonfunctioning pituitary microadenoma, parathyroid adenoma, and papillary thyroid carcinoma. Both bronchial carcinoid and parathyroid adenoma tissue showed decreased or even absent p27 protein expression, but loss of heterozygosity for the wildtype CDKN1B allele was observed only in the carcinoid sample.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001395064.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the CDKN1B protein (p.Pro69Leu). This variant is present in population databases (rs777354267, gnomAD 0.0009%). This missense change has been observed in individual(s) with multiple endocrine tumors, sarcoma, pituitary adenoma and hyperparathyroidism (PMID: 20824794, 29625052, 32386678). ClinVar contains an entry for this variant (Variation ID: 183393). 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 disruptive. Experimental studies have shown that this missense change affects CDKN1B function (PMID: 20824794). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003823115.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV005045519.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (1)

Description

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Juno Genomics, Hangzhou Juno Genomics, Inc, SCV005416189.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PM2_Supporting+PP3_Strong+PS4_Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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