ClinVar Genomic variation as it relates to human health
NM_005591.4(MRE11):c.350A>G (p.Asn117Ser)
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.
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(1); Likely pathogenic(6); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005591.4(MRE11):c.350A>G (p.Asn117Ser)
Variation ID: 8783 Accession: VCV000008783.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q21 11: 94479726 (GRCh38) [ NCBI UCSC ] 11: 94212892 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 4, 2013 Apr 15, 2024 Oct 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005591.4:c.350A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005582.1:p.Asn117Ser missense NM_001330347.2:c.350A>G NP_001317276.1:p.Asn117Ser missense NM_005590.4:c.350A>G NP_005581.2:p.Asn117Ser missense NC_000011.10:g.94479726T>C NC_000011.9:g.94212892T>C NG_007261.1:g.19149A>G LRG_85:g.19149A>G LRG_85t1:c.350A>G LRG_85p1:p.Asn117Ser P49959:p.Asn117Ser - Protein change
- N117S
- Other names
- p.N117S:AAC>AGC
- Canonical SPDI
- NC_000011.10:94479725:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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MRE11 | - | - |
GRCh38 GRCh37 |
2036 | 2070 |
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
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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. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2023 | RCV000009328.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 17, 2020 | RCV000115917.10 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2021 | RCV000212557.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 19, 2023 | RCV001034646.8 |
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
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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. |
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Likely pathogenic
(Oct 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia-like disorder 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004193776.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(May 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia-like disorder 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023517.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Apr 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia-like disorder
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000642133.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MRE11 function (PMID: 10612394, 22705791, 23080121). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 8783). This missense change has been observed in individual(s) with ataxia-telangiectasia-like disorder and/or breast cancer (PMID: 10612394, 11371508, 24030952, 28715532, 32986223). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs137852760, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 117 of the MRE11 protein (p.Asn117Ser). (less)
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Likely pathogenic
(Nov 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248582.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 4
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Pathogenic
(Jan 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia-like disorder 1
Affected status: yes
Allele origin:
inherited
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965779.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
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Likely pathogenic
(Aug 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia-like disorder 1
Affected status: yes
Allele origin:
germline
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Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV001477512.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Likely pathogenic
(May 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149826.12
First in ClinVar: May 17, 2014 Last updated: Jun 01, 2016 |
Comment:
Published functional studies suggest a damaging effect: impaired binding to Nbs1, reduced homologous recombination, reduced cell growth, abnormal nuclear localization, and decreased telomere length (Stewart … (more)
Published functional studies suggest a damaging effect: impaired binding to Nbs1, reduced homologous recombination, reduced cell growth, abnormal nuclear localization, and decreased telomere length (Stewart et al., 1999; Lee et al., 2003; Limbo et al., 2012; Schiller et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22078559, 12966088, 14532133, 15279810, 22705791, 23080121, 24030952, 15279769, 10612394, 11371508, 27535533) (less)
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Uncertain significance
(Aug 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000185772.7
First in ClinVar: Aug 06, 2014 Last updated: Dec 03, 2022 |
Comment:
The p.N117S variant (also known as c.350A>G), located in coding exon 4 of the MRE11A gene, results from an A to G substitution at nucleotide … (more)
The p.N117S variant (also known as c.350A>G), located in coding exon 4 of the MRE11A gene, results from an A to G substitution at nucleotide position 350. The asparagine at codon 117 is replaced by serine, an amino acid with highly similar properties. This variant was described in two siblings with ataxia-telangiectasia-like disorder (ATLD). Both siblings had features of ataxia-telangiectasia (A-T) and intermediate levels of radiosensitivity, but no detectable ATM mutations. Sequence analysis of cDNA combined with parental studies suggest p.N117S was in trans with a null mutation in the affected siblings (Stewart GS et al. Cell, 1999 Dec;99:577-87; Pitts SA et al. Hum. Mol. Genet., 2001 May;10:1155-62). This variant has also been reported in a child with progressive balance disorder after age 2 with dystonia and myoclonic jerks and marked atrophy of cerebellar vermis by age 12. This child was also found to carry a second MRE11A alteration, however the phase (cis or trans) of these two alterations was not determined (Németh AH et al. Brain, 2013 Oct;136:3106-18). Functional analyses of p.N117S in yeast have demonstrated growth inhibition, impaired homologous recombination, decreased telomere length, decreased MRE11 accumulation in the nucleus, and impaired Nbs1 interaction compared to wild type protein (Schiller CB et al. Nat. Struct. Mol. Biol., 2012 Jul;19:693-700; Limbo O et al. Nucleic Acids Res., 2012 Dec;40:11435-49; Park YB et al. Structure, 2011 Nov;19:1591-602). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 15, 2001)
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no assertion criteria provided
Method: literature only
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ATAXIA-TELANGIECTASIA-LIKE DISORDER 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029546.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 16, 2020 |
Comment on evidence:
In 2 brothers with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391) originally reported by Klein et al. (1996), Stewart et al. (1999) identified a heterozygous A-to-G transition at … (more)
In 2 brothers with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391) originally reported by Klein et al. (1996), Stewart et al. (1999) identified a heterozygous A-to-G transition at nucleotide 350 of the MRE11A gene, resulting in an asn117-to-ser (N117S) substitution on the paternal allele. No maternally derived mutation was detected by DNA sequencing, suggesting that the mother was heterozygous for a null MRE11A mutation. Western blotting showed reduced MRE11A levels in maternally-derived cells. The boys had early-childhood onset of progressive cerebellar degeneration causing cerebellar ataxia and oculomotor apraxia, but no telangiectasia. Pitts et al. (2001) later identified a heterozygous truncating mutation in the MRE11A gene (600814.0003) on the maternal allele. The findings confirmed autosomal recessive inheritance of the disorder. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Germline variants of Brazilian women with breast cancer and detection of a novel pathogenic ATM deletion in early-onset breast cancer. | Bandeira G | Breast cancer (Tokyo, Japan) | 2021 | PMID: 32986223 |
Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial. | Hahnen E | JAMA oncology | 2017 | PMID: 28715532 |
Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model. | Németh AH | Brain : a journal of neurology | 2013 | PMID: 24030952 |
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 |
Structure of Mre11-Nbs1 complex yields insights into ataxia-telangiectasia-like disease mutations and DNA damage signaling. | Schiller CB | Nature structural & molecular biology | 2012 | PMID: 22705791 |
Mre11 modulates the fidelity of fusion between short telomeres in human cells. | Tankimanova M | Nucleic acids research | 2012 | PMID: 22139912 |
Crystal structure of human Mre11: understanding tumorigenic mutations. | Park YB | Structure (London, England : 1993) | 2011 | PMID: 22078559 |
Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. | Bartkova J | Molecular oncology | 2008 | PMID: 19383352 |
Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility. | Heikkinen K | Journal of medical genetics | 2003 | PMID: 14684699 |
Regulation of Mre11/Rad50 by Nbs1: effects on nucleotide-dependent DNA binding and association with ataxia-telangiectasia-like disorder mutant complexes. | Lee JH | The Journal of biological chemistry | 2003 | PMID: 12966088 |
hMRE11: genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay. | Pitts SA | Human molecular genetics | 2001 | PMID: 11371508 |
Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization. | Desai-Mehta A | Molecular and cellular biology | 2001 | PMID: 11238951 |
The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. | Stewart GS | Cell | 1999 | PMID: 10612394 |
Ataxia without telangiectasia masquerading as benign hereditary chorea. | Klein C | Movement disorders : official journal of the Movement Disorder Society | 1996 | PMID: 8684395 |
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Text-mined citations for rs137852760 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.