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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ClinVar Genomic variation as it relates to human health
NM_001370259.2(MEN1):c.1618C>T (p.Pro540Ser)
Germline
Classification
Help
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.
(12)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(10); Likely benign(2)
Uncertain significance(10); Likely benign(2)
12
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001370259.2(MEN1):c.1618C>T (p.Pro540Ser)
Variation ID: 200987 Accession: VCV000200987.55
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 64804549 (GRCh38) [ NCBI UCSC ] 11: 64572021 (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 Jan 1, 2018 Oct 20, 2024 Jan 21, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370259.2:c.1618C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357188.2:p.Pro540Ser missense NM_000244.4:c.1633C>T NP_000235.3:p.Pro545Ser missense NM_001370251.2:c.1744C>T NP_001357180.2:p.Pro582Ser missense NM_001370260.2:c.1618C>T NP_001357189.2:p.Pro540Ser missense NM_001370261.2:c.1618C>T NP_001357190.2:p.Pro540Ser missense NM_001370262.2:c.1513C>T NP_001357191.2:p.Pro505Ser missense NM_001370263.2:c.1513C>T NP_001357192.2:p.Pro505Ser missense NM_130799.3:c.1618C>T NP_570711.2:p.Pro540Ser missense NM_130800.3:c.1633C>T NP_570712.2:p.Pro545Ser missense NM_130801.3:c.1633C>T NP_570713.2:p.Pro545Ser missense NM_130802.3:c.1633C>T NP_570714.2:p.Pro545Ser missense NM_130803.3:c.1633C>T NP_570715.2:p.Pro545Ser missense NM_130804.3:c.1633C>T NP_570716.2:p.Pro545Ser missense NC_000011.10:g.64804549G>A NC_000011.9:g.64572021G>A NG_008929.1:g.11746C>T NG_033040.1:g.3693C>T LRG_509:g.11746C>T LRG_509t1:c.1633C>T LRG_509p1:p.Pro545Ser LRG_509t2:c.1618C>T LRG_509p2:p.Pro540Ser - Protein change
- P540S, P545S, P505S, P582S
- Other names
- -
- Canonical SPDI
- NC_000011.10:64804548:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe 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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00012
Trans-Omics for Precision Medicine (TOPMed) 0.00020
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| MEN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2580 | 2601 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 21, 2024 | RCV000231689.24 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Aug 10, 2021 | RCV000575915.8 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 11, 2020 | RCV000679251.33 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
- | RCV000735331.4 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 29, 2019 | RCV001103324.5 |
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
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormal cerebral white matter morphology
Developmental regression Dystonic disorder Leukodystrophy
Affected status: yes
Allele origin:
germline
|
Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV000854485.2
First in ClinVar: Dec 16, 2018 Last updated: Dec 24, 2018 |
Sex: female
|
|
|
Uncertain significance
(Jul 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperparathyroidism
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001260067.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
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, … (more)
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Jul 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001260066.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
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, … (more)
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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Aug 10, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002530059.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MEN1 c.1618C>T (p.P540S) variant has been reported in several individuals with features of multiple endocrine neoplasia type 1, including pheochromocytoma, pituitary adenoma, and/or hyperparathyroidism … (more)
The MEN1 c.1618C>T (p.P540S) variant has been reported in several individuals with features of multiple endocrine neoplasia type 1, including pheochromocytoma, pituitary adenoma, and/or hyperparathyroidism (PMID: 12652570, 23321498, 31431315, 34313384, 32761341). However, it has also been reported in individuals without clinical features of multiple endocrine neoplasia (PMID: 30755392, 34313384). It was observed in 19/35416 chromosomes of the Latino subpopulation, with no homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654).The variant has been reported in ClinVar (Variation ID 200987). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
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Uncertain significance
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000838449.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
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Uncertain significance
(Jul 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003808781.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
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Likely benign
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000291288.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
|
|
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Likely benign
(Apr 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000664573.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely 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. (less)
|
|
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Uncertain significance
(Oct 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805922.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
|
|
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Uncertain significance
(Jan 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000338793.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
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Uncertain significance
(Sep 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469970.3
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
|
|
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Uncertain significance
(Sep 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248411.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
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| click to load more click to collapse | |||||
Comment:
Comment:
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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This alteration is classified as likely 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.
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:
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This alteration is classified as likely 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Dutch founder SDHB exon 3 deletion in patients with pheochromocytoma-paraganglioma in South Africa. | Gordon DM | Endocrine connections | 2022 | PMID: 34939938 |
| The recurrent p.(Pro540Ser) MEN1 genetic variant should be considered nonpathogenic: A case report. | Villabona C | American journal of medical genetics. Part A | 2021 | PMID: 34313384 |
| Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia. | Khairi S | Hormones & cancer | 2020 | PMID: 32761341 |
| 18F-FDOPA PET/CT accurately identifies MEN1-associated pheochromocytoma. | Tepede AA | Endocrinology, diabetes & metabolism case reports | 2020 | PMID: 32130200 |
| 3P association (3PAs): Pituitary adenoma and pheochromocytoma/paraganglioma. A heterogeneous clinical syndrome associated with different gene mutations. | Guerrero-Pérez F | European journal of internal medicine | 2019 | PMID: 31431315 |
| Proposition of adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants. | Romanet P | Human mutation | 2019 | PMID: 30869828 |
| A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants. | Ji J | Cold Spring Harbor molecular case studies | 2019 | PMID: 30755392 |
| Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis. | Cuny T | European journal of endocrinology | 2013 | PMID: 23321498 |
| Efficient mutation detection in MEN1 gene using a combination of single-strand conformation polymorphism (MDGA) and heteroduplex analysis. | Crépin M | Electrophoresis | 2003 | PMID: 12652570 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MEN1 | - | - | - | - |
Text-mined citations for rs745404679 ...
HelpThese 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 Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.