VCV001776456.5 - ClinVar

NM_001370259.2(MEN1):c.1614dup (p.Ala539fs)

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.

(2)

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

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.1614dup (p.Ala539fs)

Variation ID: 1776456 Accession: VCV001776456.5

Type and length

Duplication, 1 bp

Location

Cytogenetic: 11q13.1 11: 64804552-64804553 (GRCh38) [ NCBI UCSC ] 11: 64572024-64572025 (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	Nov 29, 2022	May 1, 2024	Sep 2, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001370259.2:c.1614dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001357188.2:p.Ala539fs	frameshift
NM_000244.4:c.1629dup	NP_000235.3:p.Ala544fs	frameshift
NM_001370251.2:c.1740dup	NP_001357180.2:p.Ala581fs	frameshift
NM_001370260.2:c.1614dup	NP_001357189.2:p.Ala539fs	frameshift
NM_001370261.2:c.1614dup	NP_001357190.2:p.Ala539fs	frameshift
NM_001370262.2:c.1509dup	NP_001357191.2:p.Ala504fs	frameshift
NM_001370263.2:c.1509dup	NP_001357192.2:p.Ala504fs	frameshift
NM_001407142.1:c.1740dup	NP_001394071.1:p.Ala581Serfs	frameshift
NM_001407143.1:c.1740dup	NP_001394072.1:p.Ala581Serfs	frameshift
NM_001407144.1:c.1740dup	NP_001394073.1:p.Ala581Serfs	frameshift
NM_001407145.1:c.1629dup	NP_001394074.1:p.Ala544Serfs	frameshift
NM_001407146.1:c.1614dup	NP_001394075.1:p.Ala539Serfs	frameshift
NM_001407147.1:c.1614dup	NP_001394076.1:p.Ala539Serfs	frameshift
NM_001407148.1:c.1509dup	NP_001394077.1:p.Ala504Serfs	frameshift
NM_001407149.1:c.1509dup	NP_001394078.1:p.Ala504Serfs	frameshift
NM_001407150.1:c.1755dup	NP_001394079.1:p.Ala586Serfs	frameshift
NM_001407151.1:c.1635dup	NP_001394080.1:p.Ala546Serfs	frameshift
NM_001407152.1:c.1449dup	NP_001394081.1:p.Ala484Serfs	frameshift
NM_130799.2:c.1614dupA		frameshift
NM_130799.3:c.1614dup	NP_570711.2:p.Ala539fs	frameshift
NM_130800.3:c.1629dup	NP_570712.2:p.Ala544fs	frameshift
NM_130801.3:c.1629dup	NP_570713.2:p.Ala544fs	frameshift
NM_130802.3:c.1629dup	NP_570714.2:p.Ala544fs	frameshift
NM_130803.3:c.1629dup	NP_570715.2:p.Ala544fs	frameshift
NM_130804.3:c.1629dup	NP_570716.2:p.Ala544fs	frameshift
NR_176284.1:n.1812dup
NR_176285.1:n.1824dup
NR_176286.1:n.1827dup
NR_176287.1:n.2085dup
NC_000011.10:g.64804553dup
NC_000011.9:g.64572025dup
NG_008929.1:g.11742dup
NG_033040.2:g.3661dup
LRG_509:g.11742dup
LRG_509t1:c.1629dup	LRG_509p1:p.Ala544Serfs
LRG_509t2:c.1614dup	LRG_509p2:p.Ala539Serfs

... more HGVS ... less HGVS

Protein change

A504fs, A539fs, A544fs, A581fs

Other names

Canonical SPDI

NC_000011.10:64804552:T:TT

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	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.
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 2, 2022	RCV002400951.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Aug 11, 2022	RCV003121004.3

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 (Aug 11, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV003800313.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: The MEN1 c.1614dup, p.Ala539SerfsTer18 variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is absent from the … (more) The MEN1 c.1614dup, p.Ala539SerfsTer18 variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is absent from the 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 that would include a sequence of 18 amino acid residues not usually present. Based on available information, this variant is considered to be likely pathogenic. (less)
Pathogenic (Sep 02, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002705267.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.1614dupA variant, located in coding exon 9 of the MEN1 gene, results from a duplication of A at nucleotide position 1614, causing a translational … (more) The c.1614dupA variant, located in coding exon 9 of the MEN1 gene, results from a duplication of A at nucleotide position 1614, causing a translational frameshift with a predicted alternate stop codon (p.A539Sfs*18). This alteration occurs at the 3' terminus of theMEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 72 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). 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)

Comment:

The MEN1 c.1614dup, p.Ala539SerfsTer18 variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is absent from the 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 that would include a sequence of 18 amino acid residues not usually present. Based on available information, this variant is considered to be likely pathogenic.

Comment:

The c.1614dupA variant, located in coding exon 9 of the MEN1 gene, results from a duplication of A at nucleotide position 1614, causing a translational frameshift with a predicted alternate stop codon (p.A539Sfs*18). This alteration occurs at the 3' terminus of theMEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 72 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). 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.

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 May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_001370259.2(MEN1):c.1614dup (p.Ala539fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...