This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 519 of the MEN1 protein (p.Pro519Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MEN1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MEN1 protein function. 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.
ClinVar Genomic variation as it relates to human health
NM_001370259.2(MEN1):c.1556C>T (p.Pro519Leu)
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.
(2)
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.
Uncertain significance
2
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001370259.2(MEN1):c.1556C>T (p.Pro519Leu)
Variation ID: 2771876 Accession: VCV002771876.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 64804611 (GRCh38) [ NCBI UCSC ] 11: 64572083 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 14, 2024 Jul 15, 2024 Apr 30, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370259.2:c.1556C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357188.2:p.Pro519Leu missense NM_000244.4:c.1571C>T NP_000235.3:p.Pro524Leu missense NM_001370251.2:c.1682C>T NP_001357180.2:p.Pro561Leu missense NM_001370260.2:c.1556C>T NP_001357189.2:p.Pro519Leu missense NM_001370261.2:c.1556C>T NP_001357190.2:p.Pro519Leu missense NM_001370262.2:c.1451C>T NP_001357191.2:p.Pro484Leu missense NM_001370263.2:c.1451C>T NP_001357192.2:p.Pro484Leu missense NM_001407142.1:c.1682C>T NP_001394071.1:p.Pro561Leu missense NM_001407143.1:c.1682C>T NP_001394072.1:p.Pro561Leu missense NM_001407144.1:c.1682C>T NP_001394073.1:p.Pro561Leu missense NM_001407145.1:c.1571C>T NP_001394074.1:p.Pro524Leu missense NM_001407146.1:c.1556C>T NP_001394075.1:p.Pro519Leu missense NM_001407147.1:c.1556C>T NP_001394076.1:p.Pro519Leu missense NM_001407148.1:c.1451C>T NP_001394077.1:p.Pro484Leu missense NM_001407149.1:c.1451C>T NP_001394078.1:p.Pro484Leu missense NM_001407150.1:c.1697C>T NP_001394079.1:p.Pro566Leu missense NM_001407151.1:c.1577C>T NP_001394080.1:p.Pro526Leu missense NM_001407152.1:c.1391C>T NP_001394081.1:p.Pro464Leu missense NM_130799.3:c.1556C>T NP_570711.2:p.Pro519Leu missense NM_130800.3:c.1571C>T NP_570712.2:p.Pro524Leu missense NM_130801.3:c.1571C>T NP_570713.2:p.Pro524Leu missense NM_130802.3:c.1571C>T NP_570714.2:p.Pro524Leu missense NM_130803.3:c.1571C>T NP_570715.2:p.Pro524Leu missense NM_130804.3:c.1571C>T NP_570716.2:p.Pro524Leu missense NR_176284.1:n.1754C>T non-coding transcript variant NR_176285.1:n.1766C>T non-coding transcript variant NR_176286.1:n.1769C>T non-coding transcript variant NR_176287.1:n.2027C>T non-coding transcript variant NC_000011.10:g.64804611G>A NC_000011.9:g.64572083G>A NG_008929.1:g.11684C>T NG_033040.1:g.3631C>T NG_033040.2:g.3603C>T LRG_509:g.11684C>T LRG_509t1:c.1571C>T LRG_509p1:p.Pro524Leu LRG_509t2:c.1556C>T LRG_509p2:p.Pro519Leu - Protein change
- P526L, P464L, P519L, P484L, P524L, P561L, P566L
- Other names
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- Canonical SPDI
- NC_000011.10:64804610: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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- 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. |
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| 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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
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Dec 4, 2023 | RCV003517836.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Apr 30, 2024 | RCV004587538.1 |
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. |
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Uncertain significance
(Dec 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004337034.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 519 of the MEN1 protein (p.Pro519Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 519 of the MEN1 protein (p.Pro519Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MEN1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MEN1 protein function. 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)
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Uncertain significance
(Apr 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005076412.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
Variant summary: MEN1 c.1556C>T (p.Pro519Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: MEN1 c.1556C>T (p.Pro519Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.1556C>T in individuals affected with Multiple Endocrine Neoplasia Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2771876). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
Comment:
Comment:
Variant summary: MEN1 c.1556C>T (p.Pro519Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.1556C>T in individuals affected with Multiple Endocrine Neoplasia Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2771876). Based on the evidence outlined above, the variant was classified as uncertain significance.
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 sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 519 of the MEN1 protein (p.Pro519Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MEN1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MEN1 protein function. 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:
Variant summary: MEN1 c.1556C>T (p.Pro519Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.1556C>T in individuals affected with Multiple Endocrine Neoplasia Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2771876). Based on the evidence outlined above, the variant was classified as uncertain significance.
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for this variant ...
HelpRecord last updated Sep 30, 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.