Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17555499, 22470073, 24218143, 9103196, 27846313, 15082967, 12755956, 10709111, 12016470, 11579199, 9681840, 17823710, 9709921, 29036195, 30324798, 31414909)
ClinVar Genomic variation as it relates to human health
NM_001370259.2(MEN1):c.1579C>T (p.Arg527Ter)
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.
(9)
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.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001370259.2(MEN1):c.1579C>T (p.Arg527Ter)
Variation ID: 16688 Accession: VCV000016688.36
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.1 11: 64804588 (GRCh38) [ NCBI UCSC ] 11: 64572060 (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 Apr 4, 2013 Oct 20, 2024 Nov 8, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370259.2:c.1579C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357188.2:p.Arg527Ter nonsense NM_000244.4:c.1594C>T NP_000235.3:p.Arg532Ter nonsense NM_001370251.2:c.1705C>T NP_001357180.2:p.Arg569Ter nonsense NM_001370260.2:c.1579C>T NP_001357189.2:p.Arg527Ter nonsense NM_001370261.2:c.1579C>T NP_001357190.2:p.Arg527Ter nonsense NM_001370262.2:c.1474C>T NP_001357191.2:p.Arg492Ter nonsense NM_001370263.2:c.1474C>T NP_001357192.2:p.Arg492Ter nonsense NM_130799.2:c.[1579C>T] nonsense NM_130799.3:c.1579C>T NP_570711.2:p.Arg527Ter nonsense NM_130800.3:c.1594C>T NP_570712.2:p.Arg532Ter nonsense NM_130801.3:c.1594C>T NP_570713.2:p.Arg532Ter nonsense NM_130802.3:c.1594C>T NP_570714.2:p.Arg532Ter nonsense NM_130803.3:c.1594C>T NP_570715.2:p.Arg532Ter nonsense NM_130804.3:c.1594C>T NP_570716.2:p.Arg532Ter nonsense NC_000011.10:g.64804588G>A NC_000011.9:g.64572060G>A NG_008929.1:g.11707C>T NG_033040.1:g.3654C>T LRG_509:g.11707C>T LRG_509t2:c.1579C>T LRG_509p2:p.Arg527Ter - Protein change
- R527*, R532*, R569*, R492*
- Other names
-
p.R527*:CGA>TGA
- Canonical SPDI
- NC_000011.10:64804587:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 8, 2023 | RCV000018168.25 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2023 | RCV000182423.28 | |
|
Metastatic pancreatic neuroendocrine tumours
|
Likely pathogenic (1) |
no assertion criteria provided
|
Nov 1, 2017 | RCV000515522.9 |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 15, 2021 | RCV000491431.11 |
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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|---|---|---|---|---|---|
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Pathogenic
(Sep 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234768.13
First in ClinVar: Jul 05, 2015 Last updated: Dec 19, 2017 |
Comment:
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population … (more)
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17555499, 22470073, 24218143, 9103196, 27846313, 15082967, 12755956, 10709111, 12016470, 11579199, 9681840, 17823710, 9709921, 29036195, 30324798, 31414909) (less)
|
|
|
Pathogenic
(Feb 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002050028.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The MEN1 c.1579C>T; p.Arg527Ter variant (rs104894261), also known as c.1594C>T; p.Arg532Ter in transcript NM_000244.3, is reported in the literature in multiple individuals and families affected … (more)
The MEN1 c.1579C>T; p.Arg527Ter variant (rs104894261), also known as c.1594C>T; p.Arg532Ter in transcript NM_000244.3, is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 (Carvalho 2018, Chandrasekharappa 1997, Hasani-Ranjbar 2014, Pardi 2017, Perrier 2002, Pieterman 2012). This variant has been observed to co-segregate with disease in affected members of several families (Hasani-Ranjbar 2014, Perrier 2002). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the MEN1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein missing the last 84 amino acids. Based on available information, this variant is considered to be pathogenic. References: Carvalho RA et al. Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing. Eur J Endocrinol. 2018 Dec 1;179(6):391-407. Chandrasekharappa SC et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997 Apr 18;276(5311):404-7. Hasani-Ranjbar S et al. Ectopic Cushing syndrome associated with thymic carcinoid tumor as the first presentation of MEN1 syndrome-report of a family with MEN1 gene mutation. Fam Cancer. 2014 Jun;13(2):267-72. Pardi E et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS One. 2017 Oct 16;12(10):e0186485. Perrier ND et al. Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism. World J Surg. 2002 Aug;26(8):907-13. Pieterman CR et al. Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype. Ann Surg. 2012 Jun;255(6):1171-8. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 1
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002072979.1
First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022 |
Comment:
The stop gained p.R527* in MEN1 (NM_130799.2) has been reported in previously affected patients (Pardi E et al, 2017). The p.R527* variant is novel (not … (more)
The stop gained p.R527* in MEN1 (NM_130799.2) has been reported in previously affected patients (Pardi E et al, 2017). The p.R527* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Since it is present in the last exon,it may not cause nonsense mediated decay. However since has been reported in multiple affected patients and families (Pieterman CR etal,2012; Chung YJ e 2014;Kong J et al,2016) and there are presence of downstream truncating variants (Schaaf L et al,2007), the above variant has been classfied as Pathogenic. (less)
Clinical Features:
Parathyroid gland adenoma (present) , Headache (present) , Hypothyroidism (present) , Focal T2 hypointense thalamic lesion (present)
|
|
|
Pathogenic
(Oct 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000813224.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg527*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg527*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the MEN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with multiple endocrine neoplasia type I syndrome (MEN1) and MEN1-related disease (PMID: 9103196, 9709921, 22470073, 24218143, 25309785, 27846313, 29036195). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1594C>T (p.Arg532X) and c.1689C>T. ClinVar contains an entry for this variant (Variation ID: 16688). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Gln554*) have been determined to be pathogenic (PMID: 11578300, 15331604, 16449969, 17853334). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Nov 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004827273.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
The c.1579C>T (p.Arg527*) variant in the MEN1 gene is predicted to result in an absent or truncated protein product. This variant has been reported in … (more)
The c.1579C>T (p.Arg527*) variant in the MEN1 gene is predicted to result in an absent or truncated protein product. This variant has been reported in several individuals (>10) with multiple endocrine neoplasia type 1 (MEN1) or MEN1 related diseases (PMID: 9103196, 29036195, 25309785, 9709921, 22470073, 27846313, 29092957, 32761341, 30820182, 9681840, 11303512). This variant is reported to segregate with disease in two families (PMID: 24218143, 12016470). Loss of function variants of MEN1 are known to be pathogenic (PMID: 32780883, 31044390, 32430905). Truncating variants downstream of this variant are reported in individuals with MEN1 related phenotypes (PMID: 12112656, 15714081, 17853334). This variant is found to be absent in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 16688). Therefore, the c.1579C>T (p.Arg527*) variant in the MEN1 gene is classified as pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000579759.6
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
The p.R527* pathogenic mutation (also known as c.1579C>T), located in coding exon 9 of the MEN1 gene, results from a C to T substitution at … (more)
The p.R527* pathogenic mutation (also known as c.1579C>T), located in coding exon 9 of the MEN1 gene, results from a C to T substitution at nucleotide position 1579. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of MEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 84 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been reported in multiple unrelated individuals affected with MEN1 syndrome (Chandrasekharappa S et al Science. 1997 Apr 18;276(5311):404-7; Chung YJ et al. Endocrinol Metab (Seoul). 2014 Sep;29:270-9; Pardi E et al. PLoS One. 2017 Oct;12:e0186485). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Likely pathogenic
(Jun 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004010076.12
First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024 |
Comment:
MEN1: PVS1:Strong, PM2, PS4:Moderate, PP1
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 18, 1997)
|
no assertion criteria provided
Method: literature only
|
MULTIPLE ENDOCRINE NEOPLASIA, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038447.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous nonsense mutation at codon 527 of the MEN1 gene, converting arginine to … (more)
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous nonsense mutation at codon 527 of the MEN1 gene, converting arginine to stop (R527X). (less)
|
|
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Likely pathogenic
(Nov 01, 2017)
|
no assertion criteria provided
Method: research
|
Metastatic pancreatic neuroendocrine tumours
Affected status: no
Allele origin:
somatic
|
Genome Sciences Centre, British Columbia Cancer Agency
Accession: SCV000611142.1
First in ClinVar: Nov 23, 2017 Last updated: Nov 23, 2017 |
|
Comment:
Comment:
The MEN1 c.1579C>T; p.Arg527Ter variant (rs104894261), also known as c.1594C>T; p.Arg532Ter in transcript NM_000244.3, is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 (Carvalho 2018, Chandrasekharappa 1997, Hasani-Ranjbar 2014, Pardi 2017, Perrier 2002, Pieterman 2012). This variant has been observed to co-segregate with disease in affected members of several families (Hasani-Ranjbar 2014, Perrier 2002). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the MEN1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein missing the last 84 amino acids. Based on available information, this variant is considered to be pathogenic. References: Carvalho RA et al. Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing. Eur J Endocrinol. 2018 Dec 1;179(6):391-407. Chandrasekharappa SC et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997 Apr 18;276(5311):404-7. Hasani-Ranjbar S et al. Ectopic Cushing syndrome associated with thymic carcinoid tumor as the first presentation of MEN1 syndrome-report of a family with MEN1 gene mutation. Fam Cancer. 2014 Jun;13(2):267-72. Pardi E et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS One. 2017 Oct 16;12(10):e0186485. Perrier ND et al. Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism. World J Surg. 2002 Aug;26(8):907-13. Pieterman CR et al. Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype. Ann Surg. 2012 Jun;255(6):1171-8.
Comment:
The stop gained p.R527* in MEN1 (NM_130799.2) has been reported in previously affected patients (Pardi E et al, 2017). The p.R527* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Since it is present in the last exon,it may not cause nonsense mediated decay. However since has been reported in multiple affected patients and families (Pieterman CR etal,2012; Chung YJ e 2014;Kong J et al,2016) and there are presence of downstream truncating variants (Schaaf L et al,2007), the above variant has been classfied as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg527*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the MEN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with multiple endocrine neoplasia type I syndrome (MEN1) and MEN1-related disease (PMID: 9103196, 9709921, 22470073, 24218143, 25309785, 27846313, 29036195). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1594C>T (p.Arg532X) and c.1689C>T. ClinVar contains an entry for this variant (Variation ID: 16688). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Gln554*) have been determined to be pathogenic (PMID: 11578300, 15331604, 16449969, 17853334). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1579C>T (p.Arg527*) variant in the MEN1 gene is predicted to result in an absent or truncated protein product. This variant has been reported in several individuals (>10) with multiple endocrine neoplasia type 1 (MEN1) or MEN1 related diseases (PMID: 9103196, 29036195, 25309785, 9709921, 22470073, 27846313, 29092957, 32761341, 30820182, 9681840, 11303512). This variant is reported to segregate with disease in two families (PMID: 24218143, 12016470). Loss of function variants of MEN1 are known to be pathogenic (PMID: 32780883, 31044390, 32430905). Truncating variants downstream of this variant are reported in individuals with MEN1 related phenotypes (PMID: 12112656, 15714081, 17853334). This variant is found to be absent in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 16688). Therefore, the c.1579C>T (p.Arg527*) variant in the MEN1 gene is classified as pathogenic.
Comment:
The p.R527* pathogenic mutation (also known as c.1579C>T), located in coding exon 9 of the MEN1 gene, results from a C to T substitution at nucleotide position 1579. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of MEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 84 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been reported in multiple unrelated individuals affected with MEN1 syndrome (Chandrasekharappa S et al Science. 1997 Apr 18;276(5311):404-7; Chung YJ et al. Endocrinol Metab (Seoul). 2014 Sep;29:270-9; Pardi E et al. PLoS One. 2017 Oct;12:e0186485). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
MEN1: PVS1:Strong, PM2, PS4:Moderate, PP1
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:
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17555499, 22470073, 24218143, 9103196, 27846313, 15082967, 12755956, 10709111, 12016470, 11579199, 9681840, 17823710, 9709921, 29036195, 30324798, 31414909)
Comment:
The MEN1 c.1579C>T; p.Arg527Ter variant (rs104894261), also known as c.1594C>T; p.Arg532Ter in transcript NM_000244.3, is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 (Carvalho 2018, Chandrasekharappa 1997, Hasani-Ranjbar 2014, Pardi 2017, Perrier 2002, Pieterman 2012). This variant has been observed to co-segregate with disease in affected members of several families (Hasani-Ranjbar 2014, Perrier 2002). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the MEN1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein missing the last 84 amino acids. Based on available information, this variant is considered to be pathogenic. References: Carvalho RA et al. Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing. Eur J Endocrinol. 2018 Dec 1;179(6):391-407. Chandrasekharappa SC et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997 Apr 18;276(5311):404-7. Hasani-Ranjbar S et al. Ectopic Cushing syndrome associated with thymic carcinoid tumor as the first presentation of MEN1 syndrome-report of a family with MEN1 gene mutation. Fam Cancer. 2014 Jun;13(2):267-72. Pardi E et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS One. 2017 Oct 16;12(10):e0186485. Perrier ND et al. Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism. World J Surg. 2002 Aug;26(8):907-13. Pieterman CR et al. Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype. Ann Surg. 2012 Jun;255(6):1171-8.
Comment:
The stop gained p.R527* in MEN1 (NM_130799.2) has been reported in previously affected patients (Pardi E et al, 2017). The p.R527* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Since it is present in the last exon,it may not cause nonsense mediated decay. However since has been reported in multiple affected patients and families (Pieterman CR etal,2012; Chung YJ e 2014;Kong J et al,2016) and there are presence of downstream truncating variants (Schaaf L et al,2007), the above variant has been classfied as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg527*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the MEN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with multiple endocrine neoplasia type I syndrome (MEN1) and MEN1-related disease (PMID: 9103196, 9709921, 22470073, 24218143, 25309785, 27846313, 29036195). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1594C>T (p.Arg532X) and c.1689C>T. ClinVar contains an entry for this variant (Variation ID: 16688). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Gln554*) have been determined to be pathogenic (PMID: 11578300, 15331604, 16449969, 17853334). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1579C>T (p.Arg527*) variant in the MEN1 gene is predicted to result in an absent or truncated protein product. This variant has been reported in several individuals (>10) with multiple endocrine neoplasia type 1 (MEN1) or MEN1 related diseases (PMID: 9103196, 29036195, 25309785, 9709921, 22470073, 27846313, 29092957, 32761341, 30820182, 9681840, 11303512). This variant is reported to segregate with disease in two families (PMID: 24218143, 12016470). Loss of function variants of MEN1 are known to be pathogenic (PMID: 32780883, 31044390, 32430905). Truncating variants downstream of this variant are reported in individuals with MEN1 related phenotypes (PMID: 12112656, 15714081, 17853334). This variant is found to be absent in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 16688). Therefore, the c.1579C>T (p.Arg527*) variant in the MEN1 gene is classified as pathogenic.
Comment:
The p.R527* pathogenic mutation (also known as c.1579C>T), located in coding exon 9 of the MEN1 gene, results from a C to T substitution at nucleotide position 1579. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of MEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 84 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been reported in multiple unrelated individuals affected with MEN1 syndrome (Chandrasekharappa S et al Science. 1997 Apr 18;276(5311):404-7; Chung YJ et al. Endocrinol Metab (Seoul). 2014 Sep;29:270-9; Pardi E et al. PLoS One. 2017 Oct;12:e0186485). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
MEN1: PVS1:Strong, PM2, PS4:Moderate, PP1
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Multiple Endocrine Neoplasia Type 1 (MEN1) 5'UTR Deletion, in MEN1 Family, Decreases Menin Expression. | Kooblall KG | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2021 | PMID: 32780883 |
| Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia. | Khairi S | Hormones & cancer | 2020 | PMID: 32761341 |
| Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort. | Mariathasan S | Clinical endocrinology | 2020 | PMID: 32430905 |
| True MEN1 or phenocopy? Evidence for geno-phenotypic correlations in MEN1 syndrome. | Kövesdi A | Endocrine | 2019 | PMID: 31044390 |
| Novel Mutations in Serbian MEN1 Patients: Genotype-phenotype Correlation. | Isailovic T | Journal of medical biochemistry | 2019 | PMID: 30820182 |
| Molecular characterization of metastatic pancreatic neuroendocrine tumors (PNETs) using whole-genome and transcriptome sequencing. | Wong HL | Cold Spring Harbor molecular case studies | 2018 | PMID: 29092957 |
| Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. | Pardi E | PloS one | 2017 | PMID: 29036195 |
| Clinical and Genetic Analysis of Multiple Endocrine Neoplasia Type 1-Related Primary Hyperparathyroidism in Chinese. | Kong J | PloS one | 2016 | PMID: 27846313 |
| Genetic and epigenetic analysis in korean patients with multiple endocrine neoplasia type 1. | Chung YJ | Endocrinology and metabolism (Seoul, Korea) | 2014 | PMID: 25309785 |
| Ectopic Cushing syndrome associated with thymic carcinoid tumor as the first presentation of MEN1 syndrome-report of a family with MEN1 gene mutation. | Hasani-Ranjbar S | Familial cancer | 2014 | PMID: 24218143 |
| Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype. | Pieterman CR | Annals of surgery | 2012 | PMID: 22470073 |
| Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. | Schaaf L | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2007 | PMID: 17853334 |
| Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression. | La P | Oncogene | 2006 | PMID: 16449969 |
| Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. | Klein RD | Genetics in medicine : official journal of the American College of Medical Genetics | 2005 | PMID: 15714081 |
| Direct binding of DNA by tumor suppressor menin. | La P | The Journal of biological chemistry | 2004 | PMID: 15331604 |
| Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. | Wautot V | Human mutation | 2002 | PMID: 12112656 |
| Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism. | Perrier ND | World journal of surgery | 2002 | PMID: 12016470 |
| Prospective controlled trial of a standardized meal stimulation test in the detection of pancreaticoduodenal endocrine tumours in patients with multiple endocrine neoplasia type 1. | Langer P | The British journal of surgery | 2001 | PMID: 11578300 |
| Founder effect in multiple endocrine neoplasia type 1 (MEN 1) in Finland. | Kytölä S | Journal of medical genetics | 2001 | PMID: 11303512 |
| Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. | Teh BT | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9709921 |
| Identification and characterization of the multiple endocrine neoplasia type 1 (MEN1) gene. | Guru SC | Journal of internal medicine | 1998 | PMID: 9681840 |
| Positional cloning of the gene for multiple endocrine neoplasia-type 1. | Chandrasekharappa SC | Science (New York, N.Y.) | 1997 | PMID: 9103196 |
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Text-mined citations for rs104894261 ...
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Record last updated Nov 03, 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.