This sequence change creates a premature translational stop signal (p.Arg633*) 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 (rs137852759, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia-like disorder, nephronophthisis-related ciliopathies and/or breast cancer (PMID: 8445618, 10612394, 19383352, 22863007). ClinVar contains an entry for this variant (Variation ID: 8782). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MRE11 function (PMID: 10612394, 14690604, 25040471). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_005591.4(MRE11):c.1897C>T (p.Arg633Ter)
Germline
Classification
Help
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.
(6)
Help
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
6
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.1897C>T (p.Arg633Ter)
Variation ID: 8782 Accession: VCV000008782.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q21 11: 94437206 (GRCh38) [ NCBI UCSC ] 11: 94170372 (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 4, 2013 Sep 16, 2024 Feb 6, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005591.4:c.1897C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005582.1:p.Arg633Ter nonsense NM_001330347.2:c.1894C>T NP_001317276.1:p.Arg632Ter nonsense NM_005590.4:c.1813C>T NP_005581.2:p.Arg605Ter nonsense NC_000011.10:g.94437206G>A NC_000011.9:g.94170372G>A NG_007261.1:g.61669C>T LRG_85:g.61669C>T LRG_85t1:c.1897C>T LRG_85p1:p.Arg633Ter - Protein change
- R633*, R605*, R632*
- Other names
- -
- Canonical SPDI
- NC_000011.10:94437205:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV000009327.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 13, 2021 | RCV000565698.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 14, 2023 | RCV001034660.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 30, 2023 | RCV004700210.1 |
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
(Oct 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia-like disorder
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000832713.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg633*) 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.Arg633*) 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 (rs137852759, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia-like disorder, nephronophthisis-related ciliopathies and/or breast cancer (PMID: 8445618, 10612394, 19383352, 22863007). ClinVar contains an entry for this variant (Variation ID: 8782). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MRE11 function (PMID: 10612394, 14690604, 25040471). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000662125.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.R633* pathogenic mutation (also known as c.1897C>T), located in coding exon 16 of the MRE11A gene, results from a C to T substitution at … (more)
The p.R633* pathogenic mutation (also known as c.1897C>T), located in coding exon 16 of the MRE11A gene, results from a C to T substitution at nucleotide position 1897. This changes the amino acid from an arginine to a stop codon within coding exon 16. This alteration was first described in a homozygous state in first cousins with ataxia-telangiectasia-like disorder (ATLD). Both individuals had features of A-T and increased levels of radiosensitivity, but no detectable ATM mutations (Stewart GS et al. Cell 1999; 99:577-87). The MRE11A p.R633* mutation has also been described in the homozygous state in siblings with ataxia (Chaki et al. Cell. 2012; 150:533-548). In another study, this alteration was detected in one individual with a personal and family history of breast cancer (Bartkova et al. J Mol Oncol. 2008; 2(4):296-316). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia-like disorder 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042590.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
The stop-gained variant c.1897C>T p.Arg633Ter in the MRE11 gene has been reported in the homozygous state in individuals affected with Ataxia telangiectasia and breast cancer … (more)
The stop-gained variant c.1897C>T p.Arg633Ter in the MRE11 gene has been reported in the homozygous state in individuals affected with Ataxia telangiectasia and breast cancer Taylor et al., 2015; Bartkova et al., 2008. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It has been submitted to ClinVar as Pathogenic Multiple submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the musculoskeletal system (present)
|
|
|
Pathogenic
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia-like disorder 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000807235.3
First in ClinVar: Oct 11, 2015 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jun 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005201978.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22863007, 25525159, 23912341, 10612394, 30625039, 29922827, 32832836, 31742824) (less)
|
|
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Pathogenic
(Aug 03, 2012)
|
no assertion criteria provided
Method: literature only
|
ATAXIA-TELANGIECTASIA-LIKE DISORDER 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029545.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 18, 2020 |
Comment on evidence:
In 2 first cousins with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391) from a large inbred family from Pakistan originally reported by Hernandez et al. (1993), Stewart et … (more)
In 2 first cousins with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391) from a large inbred family from Pakistan originally reported by Hernandez et al. (1993), Stewart et al. (1999) identified a homozygous C-to-T transition at nucleotide 1897 of the MRE11A gene, resulting in an arg633-to-ter (R633X) mutation. Both patients had progressive cerebellar degeneration, but neither patient showed any intellectual impairment. Chaki et al. (2012) identified a homozygous R633X mutation in 2 sibs, born of consanguineous Pakistani parents, with ataxia and cerebellar vermis hypoplasia. One patient had dysarthria and myoclonus. Although the patients were part of a larger group of patients with nephronophthisis (see, e.g., NPHP1, 256100) and related ciliopathies, neither had renal failure or retinal involvement. The mutation was found by homozygosity mapping and whole-exome sequencing. The report linked the pathogenesis of NPHP and ciliopathy to defects in DNA damage response signaling. (less)
|
Comment:
Comment:
The p.R633* pathogenic mutation (also known as c.1897C>T), located in coding exon 16 of the MRE11A gene, results from a C to T substitution at nucleotide position 1897. This changes the amino acid from an arginine to a stop codon within coding exon 16. This alteration was first described in a homozygous state in first cousins with ataxia-telangiectasia-like disorder (ATLD). Both individuals had features of A-T and increased levels of radiosensitivity, but no detectable ATM mutations (Stewart GS et al. Cell 1999; 99:577-87). The MRE11A p.R633* mutation has also been described in the homozygous state in siblings with ataxia (Chaki et al. Cell. 2012; 150:533-548). In another study, this alteration was detected in one individual with a personal and family history of breast cancer (Bartkova et al. J Mol Oncol. 2008; 2(4):296-316). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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:
The stop-gained variant c.1897C>T p.Arg633Ter in the MRE11 gene has been reported in the homozygous state in individuals affected with Ataxia telangiectasia and breast cancer Taylor et al., 2015; Bartkova et al., 2008. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It has been submitted to ClinVar as Pathogenic Multiple submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22863007, 25525159, 23912341, 10612394, 30625039, 29922827, 32832836, 31742824)
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:
This sequence change creates a premature translational stop signal (p.Arg633*) 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 (rs137852759, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia-like disorder, nephronophthisis-related ciliopathies and/or breast cancer (PMID: 8445618, 10612394, 19383352, 22863007). ClinVar contains an entry for this variant (Variation ID: 8782). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MRE11 function (PMID: 10612394, 14690604, 25040471). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R633* pathogenic mutation (also known as c.1897C>T), located in coding exon 16 of the MRE11A gene, results from a C to T substitution at nucleotide position 1897. This changes the amino acid from an arginine to a stop codon within coding exon 16. This alteration was first described in a homozygous state in first cousins with ataxia-telangiectasia-like disorder (ATLD). Both individuals had features of A-T and increased levels of radiosensitivity, but no detectable ATM mutations (Stewart GS et al. Cell 1999; 99:577-87). The MRE11A p.R633* mutation has also been described in the homozygous state in siblings with ataxia (Chaki et al. Cell. 2012; 150:533-548). In another study, this alteration was detected in one individual with a personal and family history of breast cancer (Bartkova et al. J Mol Oncol. 2008; 2(4):296-316). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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:
The stop-gained variant c.1897C>T p.Arg633Ter in the MRE11 gene has been reported in the homozygous state in individuals affected with Ataxia telangiectasia and breast cancer Taylor et al., 2015; Bartkova et al., 2008. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It has been submitted to ClinVar as Pathogenic Multiple submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22863007, 25525159, 23912341, 10612394, 30625039, 29922827, 32832836, 31742824)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry. | Matejcic M | JCO precision oncology | 2020 | PMID: 32832836 |
| Ataxia telangiectasia: more variation at clinical and cellular levels. | Taylor AM | Clinical genetics | 2015 | PMID: 25040471 |
| 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 |
| Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. | Chaki M | Cell | 2012 | PMID: 22863007 |
| 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 |
| Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice. | Theunissen JW | Molecular cell | 2003 | PMID: 14690604 |
| The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. | Stewart GS | Cell | 1999 | PMID: 10612394 |
| A family showing no evidence of linkage between the ataxia telangiectasia gene and chromosome 11q22-23. | Hernandez D | Journal of medical genetics | 1993 | PMID: 8445618 |
Text-mined citations for rs137852759 ...
HelpThese 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 Sep 29, 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.