VCV000183393.15 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 183393 Accession: VCV000183393.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p13.1 12: 12718045 (GRCh38) [ NCBI UCSC ] 12: 12870979 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 12, 2017	Jun 2, 2024	May 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004064.5:c.206C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004055.1:p.Pro69Leu	missense
NC_000012.12:g.12718045C>T
NC_000012.11:g.12870979C>T
NG_016341.1:g.5678C>T
	P46527:p.Pro69Leu

... more HGVS ... less HGVS

Protein change

P69L

Other names

Canonical SPDI

NC_000012.12:12718044:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

Links

ClinGen: CA186090 UniProtKB: P46527#VAR_064429 OMIM: 600778.0003 dbSNP: rs777354267 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CDKN1B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	940	991

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Multiple endocrine neoplasia type 4	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	May 27, 2024	RCV000162207.15
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Dec 14, 2023	RCV002415708.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Nov 08, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Multiple endocrine neoplasia type 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001395064.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 20824794‚ 29625052‚ 32386678 Comment: 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). … (more) 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. (less)
Uncertain significance (Apr 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple endocrine neoplasia type 4 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003823115.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Dec 14, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002727686.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 20824794 Comment: The p.P69L variant (also known as c.206C>T), located in coding exon 1 of the CDKN1B gene, results from a C to T substitution at nucleotide … (more) The p.P69L variant (also known as c.206C>T), located in coding exon 1 of the CDKN1B gene, results from a C to T substitution at nucleotide position 206. The proline at codon 69 is replaced by leucine, an amino acid with similar properties. This variant has been reported in an individual with papillary thyroid carcinoma, nonfunctioning pituitary microadenoma, as well as other comorbidities; in vitro fuctional studies showed this variant resulted in consistently reduced expression and slightly faster degradation compared to wild type (Molatore S et al. Hum. Mutat., 2010 Nov;31:E1825-35). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (May 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple endocrine neoplasia type 4 (Autosomal dominant inheritance) Affected status: no Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV005045519.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Comment: 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). … (more) 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. (less) Age: 30-39 years Sex: male
Pathogenic (Nov 01, 2010)	no assertion criteria provided Method: literature only	MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV Affected status: not provided Allele origin: germline	OMIM Accession: SCV000212164.4 First in ClinVar: Mar 16, 2015 Last updated: Jan 26, 2024	Publications: PubMed (1) PubMed: 20824794 Comment on evidence: 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 … (more) 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. (less)

Comment:

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.

Comment:

The p.P69L variant (also known as c.206C>T), located in coding exon 1 of the CDKN1B gene, results from a C to T substitution at nucleotide position 206. The proline at codon 69 is replaced by leucine, an amino acid with similar properties. This variant has been reported in an individual with papillary thyroid carcinoma, nonfunctioning pituitary microadenoma, as well as other comorbidities; in vitro fuctional studies showed this variant resulted in consistently reduced expression and slightly faster degradation compared to wild type (Molatore S et al. Hum. Mutat., 2010 Nov;31:E1825-35). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Multiple Endocrine Neoplasia Type 4: Novel CDNK1B variant and immune anomalies.	Chevalier B	Annales d'endocrinologie	2020	PMID: 32386678
Pathogenic Germline Variants in 10,389 Adult Cancers.	Huang KL	Cell	2018	PMID: 29625052
A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization.	Molatore S	Human mutation	2010	PMID: 20824794

Text-mined citations for rs777354267 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs777354267 ...