NM_001370259.2(MEN1):c.783+1G>A AND Multiple endocrine neoplasia, type 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 8, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000697334.10

Allele description [Variation Report for NM_001370259.2(MEN1):c.783+1G>A]

NM_001370259.2(MEN1):c.783+1G>A

Gene:

MEN1:menin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.1

Genomic location:

Preferred name:

NM_001370259.2(MEN1):c.783+1G>A

HGVS:

NC_000011.10:g.64807551C>T
NG_008929.1:g.8744G>A
NG_033040.1:g.691G>A
NG_033040.2:g.663G>A
NM_000244.4:c.798+1G>A
NM_001370251.2:c.783+1G>A
NM_001370259.2:c.783+1G>AMANE SELECT
NM_001370260.2:c.783+1G>A
NM_001370261.2:c.783+1G>A
NM_001370262.2:c.678+1G>A
NM_001370263.2:c.678+1G>A
NM_001407142.1:c.783+1G>A
NM_001407143.1:c.783+1G>A
NM_001407144.1:c.783+1G>A
NM_001407145.1:c.798+1G>A
NM_001407146.1:c.783+1G>A
NM_001407147.1:c.783+1G>A
NM_001407148.1:c.678+1G>A
NM_001407149.1:c.678+1G>A
NM_001407150.1:c.798+1G>A
NM_001407151.1:c.678+1G>A
NM_001407152.1:c.783+1G>A
NM_130799.3:c.783+1G>A
NM_130800.3:c.798+1G>A
NM_130801.3:c.798+1G>A
NM_130802.3:c.798+1G>A
NM_130803.3:c.798+1G>A
NM_130804.3:c.798+1G>A
LRG_509t2:c.783+1G>A
LRG_509:g.8744G>A
NC_000011.9:g.64575023C>T
NM_130799.2:c.783+1G>A
NM_130804.2:c.798+1G>A

Links:

dbSNP: rs794728652

NCBI 1000 Genomes Browser:

rs794728652

Molecular consequence:

NM_000244.4:c.798+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370251.2:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370259.2:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370260.2:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370261.2:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370262.2:c.678+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370263.2:c.678+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407142.1:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407143.1:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407144.1:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407145.1:c.798+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407146.1:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407147.1:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407148.1:c.678+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407149.1:c.678+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407150.1:c.798+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407151.1:c.678+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407152.1:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_130799.3:c.783+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_130800.3:c.798+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_130801.3:c.798+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_130802.3:c.798+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_130803.3:c.798+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_130804.3:c.798+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Multiple endocrine neoplasia, type 1 (MEN1)
Synonyms:: MEA I; MEN I; Endocrine adenomatosis multiple; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007540; MeSH: D018761; MedGen: C0025267; Orphanet: 652; OMIM: 131100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000825936	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 8, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16199547, 12112656, 17853334, 10664520, 22666734, 9683585, 9888389, 28492532
SCV002547633	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 2, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11579199, 10762295, 10664520, 15464422, 15281352, 23334809, 30364322 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000825936

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 8, 2022)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV002547633

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 2, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

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, Vercherat C, Lespinasse J, Chambe B, Lenoir GM, Zhang CX, Porchet N, Cordier M, Béroud C, Calender A.

Hum Mutat. 2002 Jul;20(1):35-47.

PubMed [citation]

PMID:: 12112656

See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000825936.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change affects a donor splice site in intron 4 of the MEN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 10664520, 22666734). This variant is also known as c.893+1G>A or IVS4+1T>A. ClinVar contains an entry for this variant (Variation ID: 428081). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.783+1G>C and c.783+1G>T nucleotide in the MEN1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9683585, 9888389). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002547633.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: MEN1 c.783+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in exon skipping (Hai_2000). The variant allele was found at a frequency of 4e-06 in 251124 control chromosomes. c.783+1G>A has been reported in the literature (as 893+1G>A or IVS4+1G>A) in individuals affected with Multiple Endocrine Neoplasia Type 1 (example, Hai_2000, Marini_2018, Nunes_2014). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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