VCV003076045.1 - ClinVar

NM_001370259.2(MEN1):c.1270dup (p.Glu424fs)

Germline

Classification

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001370259.2(MEN1):c.1270dup (p.Glu424fs)

Variation ID: 3076045 Accession: VCV003076045.1

Type and length

Duplication, 1 bp

Location

Cytogenetic: 11q13.1 11: 64805113-64805114 (GRCh38) [ NCBI UCSC ] 11: 64572585-64572586 (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 20, 2024	Apr 20, 2024	Jan 28, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NM_001370259.2:c.1270dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001357188.2:p.Glu424fs	frameshift
NM_000244.4:c.1285dup	NP_000235.3:p.Glu429fs	frameshift
NM_001370251.2:c.1396dup	NP_001357180.2:p.Glu466fs	frameshift
NM_001370260.2:c.1270dup	NP_001357189.2:p.Glu424fs	frameshift
NM_001370261.2:c.1270dup	NP_001357190.2:p.Glu424fs	frameshift
NM_001370262.2:c.1165dup	NP_001357191.2:p.Glu389fs	frameshift
NM_001370263.2:c.1165dup	NP_001357192.2:p.Glu389fs	frameshift
NM_001407142.1:c.1396dup	NP_001394071.1:p.Glu466fs	frameshift
NM_001407143.1:c.1396dup	NP_001394072.1:p.Glu466fs	frameshift
NM_001407144.1:c.1396dup	NP_001394073.1:p.Glu466fs	frameshift
NM_001407145.1:c.1285dup	NP_001394074.1:p.Glu429fs	frameshift
NM_001407146.1:c.1270dup	NP_001394075.1:p.Glu424fs	frameshift
NM_001407147.1:c.1270dup	NP_001394076.1:p.Glu424fs	frameshift
NM_001407148.1:c.1165dup	NP_001394077.1:p.Glu389fs	frameshift
NM_001407149.1:c.1165dup	NP_001394078.1:p.Glu389fs	frameshift
NM_001407150.1:c.1411dup	NP_001394079.1:p.Glu471fs	frameshift
NM_001407151.1:c.1291dup	NP_001394080.1:p.Glu431fs	frameshift
NM_001407152.1:c.1186-298dup		intron variant
NM_130799.3:c.1270dup	NP_570711.2:p.Glu424fs	frameshift
NM_130800.3:c.1285dup	NP_570712.2:p.Glu429fs	frameshift
NM_130801.3:c.1285dup	NP_570713.2:p.Glu429fs	frameshift
NM_130802.3:c.1285dup	NP_570714.2:p.Glu429fs	frameshift
NM_130803.3:c.1285dup	NP_570715.2:p.Glu429fs	frameshift
NM_130804.3:c.1285dup	NP_570716.2:p.Glu429fs	frameshift
NR_176284.1:n.1468dup		non-coding transcript variant
NR_176285.1:n.1480dup		non-coding transcript variant
NR_176286.1:n.1483dup		non-coding transcript variant
NR_176287.1:n.1741dup		non-coding transcript variant
NC_000011.10:g.64805116dup
NC_000011.9:g.64572588dup
NG_008929.1:g.11181dup
NG_033040.1:g.3128dup
NG_033040.2:g.3100dup
LRG_509:g.11181dup
LRG_509t1:c.1283dup	LRG_509p1:p.Glu429Glyfs
LRG_509t2:c.1268dup	LRG_509p2:p.Glu424Glyfs

... more HGVS ... less HGVS

Protein change

E389fs, E424fs, E429fs, E431fs, E466fs, E471fs

Other names

Canonical SPDI

NC_000011.10:64805113:CCC:CCCC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

VarSome

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
Gene	OMIM	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	2581	2602

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.
Multiple endocrine neoplasia, type 1	Likely pathogenic (1)	criteria provided, single submitter	Jan 28, 2019	RCV004018363.2

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.
Likely Pathogenic (Jan 28, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple endocrine neoplasia, type 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848111.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Glu429fs variant in MEN1 has not been previously reported in individuals with multiple endocrine neoplasia type 1 and was absent from large population studies. … (more) The p.Glu429fs variant in MEN1 has not been previously reported in individuals with multiple endocrine neoplasia type 1 and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 429 and leads to a premature termination codon 25 amino acids downstream. This alteration removes the nuclear localization signals and is predicted to lead to an absent protein or a truncated protein that is unable to translocate to the nucleus, with consequent loss of menin functionality. Heterozygous loss of function of function of the MEN1 gene is an established disease mechanism in multiple endocrine neoplasia type 1. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu429fs variant is likely pathogenic. (less)

Comment:

The p.Glu429fs variant in MEN1 has not been previously reported in individuals with multiple endocrine neoplasia type 1 and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 429 and leads to a premature termination codon 25 amino acids downstream. This alteration removes the nuclear localization signals and is predicted to lead to an absent protein or a truncated protein that is unable to translocate to the nucleus, with consequent loss of menin functionality. Heterozygous loss of function of function of the MEN1 gene is an established disease mechanism in multiple endocrine neoplasia type 1. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu429fs variant is likely pathogenic.

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:

Citations for germline classification of this variant

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 ...

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_001370259.2(MEN1):c.1270dup (p.Glu424fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...