NM_005591.4(MRE11):c.1516G>T (p.Glu506Ter) AND Ataxia-telangiectasia-like disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 5, 2024
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:: RCV000797374.8

Allele description [Variation Report for NM_005591.4(MRE11):c.1516G>T (p.Glu506Ter)]

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

Gene:

MRE11:MRE11 homolog, double strand break repair nuclease [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q21

Genomic location:

Preferred name:

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

HGVS:

NC_000011.10:g.94456323C>A
NG_007261.1:g.42552G>T
NM_001330347.2:c.1516G>T
NM_005590.4:c.1516G>T
NM_005591.4:c.1516G>TMANE SELECT
NP_001317276.1:p.Glu506Ter
NP_005581.2:p.Glu506Ter
NP_005582.1:p.Glu506Ter
NP_005582.1:p.Glu506Ter
LRG_85t1:c.1516G>T
LRG_85:g.42552G>T
LRG_85p1:p.Glu506Ter
NC_000011.9:g.94189489C>A
NM_005590.3:c.1516G>T
NM_005591.3:c.1516G>T
p.E506*

Protein change:

E506*

Links:

dbSNP: rs587781384

NCBI 1000 Genomes Browser:

rs587781384

Molecular consequence:

NM_001330347.2:c.1516G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_005590.4:c.1516G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_005591.4:c.1516G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Ataxia-telangiectasia-like disorder (ATLD)
Identifiers:: MONDO: MONDO:0011457; MedGen: C1858391; OMIM: PS604391

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000936928	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23080121, 23912341, 24763289, 26786923, 26845104, 28125075, 28492532
SCV004812942	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000936928

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 16, 2024)

germline

clinical testing

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

SCV004812942

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Feb 5, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Mre11 ATLD17/18 mutation retains Tel1/ATM activity but blocks DNA double-strand break repair.

Limbo O, Moiani D, Kertokalio A, Wyman C, Tainer JA, Russell P.

Nucleic Acids Res. 2012 Dec;40(22):11435-49. doi: 10.1093/nar/gks954. Epub 2012 Oct 17.

PubMed [citation]

PMID:: 23080121
PMCID:: PMC3526295

Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms.

Regal JA, Festerling TA, Buis JM, Ferguson DO.

Hum Mol Genet. 2013 Dec 20;22(25):5146-59. doi: 10.1093/hmg/ddt368. Epub 2013 Aug 2.

PubMed [citation]

PMID:: 23912341
PMCID:: PMC3842175

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000936928.5

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

Description

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.

#	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, SCV004812942.1

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

Description

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.

#	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: Oct 20, 2024

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