VCV000140941.43 - ClinVar

NM_005591.4(MRE11):c.1516G>T (p.Glu506Ter)

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.

(7)

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_005591.4(MRE11):c.1516G>T (p.Glu506Ter)

Variation ID: 140941 Accession: VCV000140941.43

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q21 11: 94456323 (GRCh38) [ NCBI UCSC ] 11: 94189489 (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	Mar 20, 2016	Oct 20, 2024	Mar 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005591.4:c.1516G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005582.1:p.Glu506Ter	nonsense
NM_001330347.2:c.1516G>T	NP_001317276.1:p.Glu506Ter	nonsense
NM_005590.4:c.1516G>T	NP_005581.2:p.Glu506Ter	nonsense
NC_000011.10:g.94456323C>A
NC_000011.9:g.94189489C>A
NG_007261.1:g.42552G>T
LRG_85:g.42552G>T
LRG_85t1:c.1516G>T	LRG_85p1:p.Glu506Ter

... more HGVS ... less HGVS

Protein change

E506*

Other names

Canonical SPDI

NC_000011.10:94456322:C:A

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

Links

ClinGen: CA163970 dbSNP: rs587781384 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.
MRE11		-	-	GRCh38 GRCh37	2145	2181

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 (2)	criteria provided, single submitter	Dec 13, 2023	RCV000129216.14
not provided	Pathogenic (1)	criteria provided, single submitter	Mar 1, 2024	RCV000513255.24
Ataxia-telangiectasia-like disorder 1	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 14, 2024	RCV000988624.4
Ataxia-telangiectasia-like disorder	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000797374.8

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.
Pathogenic (Dec 13, 2023)	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: SCV000183967.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: The p.E506* pathogenic mutation (also known as c.1516G>T), located in coding exon 13 of the MRE11A gene, results from a G to T substitution at … (more) The p.E506* pathogenic mutation (also known as c.1516G>T), located in coding exon 13 of the MRE11A gene, results from a G to T substitution at nucleotide position 1516. This changes the amino acid from a glutamic acid to a stop codon within coding exon 13. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Likely pathogenic (Feb 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia-like disorder 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004193770.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Ataxia-telangiectasia-like disorder 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138408.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Jan 16, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Ataxia-telangiectasia-like disorder Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000936928.5 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 23080121‚ 23912341‚ 24763289‚ 26786923‚ 26845104‚ 28125075 Comment: This sequence change creates a premature translational stop signal (p.Glu506) in the MRE11 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Glu506) in the MRE11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MRE11 are known to be pathogenic (PMID: 23080121, 23912341). This variant is present in population databases (rs587781384, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer, fallopian tube cancer, and lung cancer (PMID: 24763289, 26786923, 26845104, 28125075). ClinVar contains an entry for this variant (Variation ID: 140941). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 05, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Ataxia-telangiectasia-like disorder Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004812942.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (1) PubMed: 33426167 Comment: Variant summary: MRE11 c.1516G>T (p.Glu506X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: MRE11 c.1516G>T (p.Glu506X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 250580 control chromosomes. c.1516G>T has been reported in the literature in individuals affected with Ataxia Telangiectasia-Like Disorder (Raslan_2021) . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33426167). ClinVar contains an entry for this variant (Variation ID: 140941). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Mar 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000608613.31 First in ClinVar: Oct 30, 2017 Last updated: Oct 20, 2024	Comment: MRE11: PVS1, PM2 Number of individuals with the variant: 3
Uncertain significance (Nov 20, 2015)	Flagged submission flagged submission (Shirts et al. (Genet Med 2016)) Method: clinical testing Reason: Older and outlier claim with insufficient supporting evidence Source: ClinGen	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266186.1 First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016	Number of individuals with the variant: 1 Clinical Features: fallopian tube cancer (present) Age: 50-59 years
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

The p.E506* pathogenic mutation (also known as c.1516G>T), located in coding exon 13 of the MRE11A gene, results from a G to T substitution at nucleotide position 1516. This changes the amino acid from a glutamic acid to a stop codon within coding exon 13. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change creates a premature translational stop signal (p.Glu506*) in the MRE11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MRE11 are known to be pathogenic (PMID: 23080121, 23912341). This variant is present in population databases (rs587781384, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer, fallopian tube cancer, and lung cancer (PMID: 24763289, 26786923, 26845104, 28125075). ClinVar contains an entry for this variant (Variation ID: 140941). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: MRE11 c.1516G>T (p.Glu506X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 250580 control chromosomes. c.1516G>T has been reported in the literature in individuals affected with Ataxia Telangiectasia-Like Disorder (Raslan_2021) . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33426167). ClinVar contains an entry for this variant (Variation ID: 140941). Based on the evidence outlined above, the variant was classified as 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

Title	Author	Journal	Year	Link
Beyond Typical Ataxia Telangiectasia: How to Identify the Ataxia Telangiectasia-Like Disorders.	Raslan IR	Movement disorders clinical practice	2020	PMID: 33426167
Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study.	Ghazani AA	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28125075
Improving performance of multigene panels for genomic analysis of cancer predisposition.	Shirts BH	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26845104
Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care.	Thompson ER	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2016	PMID: 26786923
Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients.	LaDuca H	Genetics in medicine : official journal of the American College of Medical Genetics	2014	PMID: 24763289
Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms.	Regal JA	Human molecular genetics	2013	PMID: 23912341
Mre11 ATLD17/18 mutation retains Tel1/ATM activity but blocks DNA double-strand break repair.	Limbo O	Nucleic acids research	2012	PMID: 23080121

Text-mined citations for rs587781384 ...

These 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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_005591.4(MRE11):c.1516G>T (p.Glu506Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587781384 ...