Canonical splice site variant expected to result in aberrant splicing; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate in-frame loss of 35 amino acids disrupting TGF-B signaling and leading to reduced activation of p15 and p21 as well as increased cell proliferation (Canaff et al., 2012); This variant is associated with the following publications: (PMID: 22275377, 25733923, 30339208, 28870973)
ClinVar Genomic variation as it relates to human health
NM_001370259.2(MEN1):c.654+1G>A
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.
(4)
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
4
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.654+1G>A
Variation ID: 39763 Accession: VCV000039763.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 64807890 (GRCh38) [ NCBI UCSC ] 11: 64575362 (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 25, 2017 May 1, 2024 Jan 12, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- -
- Other names
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IVS3DS, G-A, +1
- Canonical SPDI
- NC_000011.10:64807889:C:T
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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.
- -
- Links
- Comment on variant
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 |
2590 | 2610 | |
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 (2) |
criteria provided, single submitter
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Jan 18, 2019 | RCV000032982.11 | |
| Pathogenic (1) |
criteria provided, single submitter
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Aug 25, 2020 | RCV002362604.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 12, 2023 | RCV002510773.1 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jan 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002820519.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
Canonical splice site variant expected to result in aberrant splicing; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate in-frame … (more)
Canonical splice site variant expected to result in aberrant splicing; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate in-frame loss of 35 amino acids disrupting TGF-B signaling and leading to reduced activation of p15 and p21 as well as increased cell proliferation (Canaff et al., 2012); This variant is associated with the following publications: (PMID: 22275377, 25733923, 30339208, 28870973) (less)
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Pathogenic
(Jan 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001207420.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: … (more)
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 22275377). This variant has been observed in several individuals and families affected with clinical features of multiple endocrine neoplasia type 1 (MEN1) syndrome (PMID: 22275377, 25733923, 28870973). This variant is also known as IVS3+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 39763). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the MEN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. (less)
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Pathogenic
(Aug 25, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002660199.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.654+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the MEN1 gene. This alteration has … (more)
The c.654+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the MEN1 gene. This alteration has been detected in an individual with multiple endocrine neoplasia type 1 (MEN1) syndrome (Canaff L et al. J. Biol. Chem., 2012 Mar;287:8584-97). RNA studies showed that the c.654+1G>A variant leads to an alternatively spliced transcript with a 35 amino acid deletion (Canaff L et al. J. Biol. Chem., 2012 Mar;287:8584-97). In addition, functional studies conducted by this same group showed that lymphoblastoid cells expressing the resulting mutant protein showed increased cell proliferation and had a defective TGF-β response. Another variant at this donor site, c.654+1G>T, has also been detected in multiple unrelated families with MEN1 (Teh BT et al. J. Clin. Endocrinol. Metab., 1998 Aug;83:2621-6; Ambry Internal Data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Mar 09, 2012)
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no assertion criteria provided
Method: literature only
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MULTIPLE ENDOCRINE NEOPLASIA, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000056761.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment on evidence:
In affected members of a 3-generation family with MEN1 (131100), Canaff et al. (2012) identified a heterozygous G-to-A transition in intron 3 of the MEN1 … (more)
In affected members of a 3-generation family with MEN1 (131100), Canaff et al. (2012) identified a heterozygous G-to-A transition in intron 3 of the MEN1 gene. Patient lymphoblastoid cells showed a wildtype transcript as well as an aberrant transcript with an in-frame deletion of 35 amino acids (184_218). In vitro studies and studies in patient cells showed that the mutant transcript was expressed and able to mediate the normal inhibition of the activity of some transcriptional regulators, including JunD (165162). However, it was defective in mediating TGF-beta (190180)-stimulated Smad3 (603109) tumor suppressor activity. Patient lymphoblastoid cells proliferated faster and were less responsive to the cytostatic effects of TGF-beta than cells from an unaffected family member. Canaff et al. (2012) concluded that this mutant menin isoform causes loss of control of cell proliferation via the selective loss of the TGF-beta signaling pathway, contributing to the development of MEN1. (less)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 22275377). This variant has been observed in several individuals and families affected with clinical features of multiple endocrine neoplasia type 1 (MEN1) syndrome (PMID: 22275377, 25733923, 28870973). This variant is also known as IVS3+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 39763). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the MEN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Comment:
The c.654+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the MEN1 gene. This alteration has been detected in an individual with multiple endocrine neoplasia type 1 (MEN1) syndrome (Canaff L et al. J. Biol. Chem., 2012 Mar;287:8584-97). RNA studies showed that the c.654+1G>A variant leads to an alternatively spliced transcript with a 35 amino acid deletion (Canaff L et al. J. Biol. Chem., 2012 Mar;287:8584-97). In addition, functional studies conducted by this same group showed that lymphoblastoid cells expressing the resulting mutant protein showed increased cell proliferation and had a defective TGF-β response. Another variant at this donor site, c.654+1G>T, has also been detected in multiple unrelated families with MEN1 (Teh BT et al. J. Clin. Endocrinol. Metab., 1998 Aug;83:2621-6; Ambry Internal Data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
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:
Canonical splice site variant expected to result in aberrant splicing; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate in-frame loss of 35 amino acids disrupting TGF-B signaling and leading to reduced activation of p15 and p21 as well as increased cell proliferation (Canaff et al., 2012); This variant is associated with the following publications: (PMID: 22275377, 25733923, 30339208, 28870973)
Comment:
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 22275377). This variant has been observed in several individuals and families affected with clinical features of multiple endocrine neoplasia type 1 (MEN1) syndrome (PMID: 22275377, 25733923, 28870973). This variant is also known as IVS3+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 39763). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the MEN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Comment:
The c.654+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the MEN1 gene. This alteration has been detected in an individual with multiple endocrine neoplasia type 1 (MEN1) syndrome (Canaff L et al. J. Biol. Chem., 2012 Mar;287:8584-97). RNA studies showed that the c.654+1G>A variant leads to an alternatively spliced transcript with a 35 amino acid deletion (Canaff L et al. J. Biol. Chem., 2012 Mar;287:8584-97). In addition, functional studies conducted by this same group showed that lymphoblastoid cells expressing the resulting mutant protein showed increased cell proliferation and had a defective TGF-β response. Another variant at this donor site, c.654+1G>T, has also been detected in multiple unrelated families with MEN1 (Teh BT et al. J. Clin. Endocrinol. Metab., 1998 Aug;83:2621-6; Ambry Internal Data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Primary hyperparathyroidism in young patients in Russia: high frequency of hyperparathyroidism-jaw tumor syndrome. | Mamedova E | Endocrine connections | 2017 | PMID: 28870973 |
| Bilateral granulosa cell tumors: a novel malignant manifestation of multiple endocrine neoplasia 1 syndrome found in a patient with a rare menin in-frame deletion. | Hall MJ | The application of clinical genetics | 2015 | PMID: 25733923 |
| Impaired transforming growth factor-β (TGF-β) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1). | Canaff L | The Journal of biological chemistry | 2012 | PMID: 22275377 |
| 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 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| 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 |
Text-mined citations for rs794728622 ...
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 Sep 29, 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.
ClinGen staff contributed the HGVS expression for this variant.