ClinVar Genomic variation as it relates to human health
NM_005591.4(MRE11):c.1090C>T (p.Arg364Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005591.4(MRE11):c.1090C>T (p.Arg364Ter)
Variation ID: 140953 Accession: VCV000140953.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q21 11: 94467821 (GRCh38) [ NCBI UCSC ] 11: 94200987 (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 Jul 15, 2018 May 19, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005591.4:c.1090C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005582.1:p.Arg364Ter nonsense NM_001330347.2:c.1090C>T NP_001317276.1:p.Arg364Ter nonsense NM_005590.4:c.1090C>T NP_005581.2:p.Arg364Ter nonsense NC_000011.10:g.94467821G>A NC_000011.9:g.94200987G>A NG_007261.1:g.31054C>T LRG_85:g.31054C>T LRG_85t1:c.1090C>T LRG_85p1:p.Arg364Ter - Protein change
- R364*
- Other names
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- Canonical SPDI
- NC_000011.10:94467820:G:A
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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 |
2098 | 2134 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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 (1) |
criteria provided, single submitter
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Dec 12, 2022 | RCV000129234.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 21, 2024 | RCV000791403.7 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 20, 2023 | RCV000662680.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 1, 2019 | RCV001092185.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 5, 2022 | RCV002509233.2 |
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
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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
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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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Pathogenic
(Mar 20, 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: SCV004193865.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 12, 2022)
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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: SCV000183989.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.R364* pathogenic mutation (also known as c.1090C>T), located in coding exon 9 of the MRE11A gene, results from a C to T substitution at … (more)
The p.R364* pathogenic mutation (also known as c.1090C>T), located in coding exon 9 of the MRE11A gene, results from a C to T substitution at nucleotide position 1090. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation was reported in an individual with a personal and family history breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug; 17(8):630-8). This mutation, designated p.Arg364Ter, was also identified in an Asian Indian woman with breast cancer and a family history of breast and endometrial cancers (Sharma Bhai P et al. Breast Care (Basel), 2017 May;12:114-116). 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)
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Pathogenic
(Aug 03, 2017)
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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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Counsyl
Accession: SCV000785388.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Pathogenic
(Dec 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819270.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: MRE11 c.1090C>T (p.Arg364X) 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.1090C>T (p.Arg364X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 5.2e-05 in 251384 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in MRE11 causing Hereditary Breast and Ovarian Cancer (HBOC) Syndrome (6.3e-05). The variant, c.1090C>T, has been reported in the literature in several individuals affected with HBOC and other tumor phenotypes (e.g. LaDuca_2014, Sharma Bhai_2017, Maxwell_2017, Hartman_2020, Zhou_2020, and Walsh_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 09, 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: SCV002017543.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 21, 2024)
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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: SCV000260355.9
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg364*) 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.Arg364*) 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 (rs371077728, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with hereditary cancer (PMID: 24763289). ClinVar contains an entry for this variant (Variation ID: 140953). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 2019)
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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: SCV001248581.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 01, 2023)
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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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New York Genome Center
Study: PrenatalSEQ
Accession: SCV005044168.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024 |
Comment:
The inherited c.1090C>T, p.(Arg364Ter) variant identified in the MRE11 gene is a nonsense variant leading to the premature termination of the protein at amino acid … (more)
The inherited c.1090C>T, p.(Arg364Ter) variant identified in the MRE11 gene is a nonsense variant leading to the premature termination of the protein at amino acid 364/709 (exon 10/20), and is expected to undergo nonsense mediated decay. This variant occurs upstream of the Helix-Loop-Helix and GAR domains of MRE11 which include regions that are critical for both RAD50 and DNA binding (for Review, [PMID:36358700]). This variant is found with low frequency in population databases (gnomADv3.1.2, gnomADv2.1.1, BRAVO-TOPMed and All of Us) with highest allele frequency of 5.2e-5 (14 heterozygotes; 0 homozygotes, gnomADv2.1.1). The c.1090C>T, p.(Arg364Ter) variant is reported in ClinVar as Pathogenic (VarID:140953; 2 stars, 5 submissions, no conflicts) and has been reported in the literature in individuals with hereditary cancer predisposition [PMID:24763289, 25503501, 27153395, 28559769]. Additional nonsense and frameshift variants downstream of the one identified here have also been reported in ClinVar as Pathogenic (VarIDs:8782, 1681558, 820257, 481748, others), and reported in individuals with Ataxia-Telangiectasia-like Disorder [PMID:33426167, 11371508]. The inherited c.1090C>T, p.(Arg364Ter) variant identified in the MRE11 gene is reported here as Pathogenic. (less)
Clinical Features:
Flat occiput (present) , Microcephaly (present)
Age: 20-29 weeks gestation
Secondary finding: no
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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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Inherited predisposition to breast cancer in the Carolina Breast Cancer Study. | Walsh T | NPJ breast cancer | 2021 | PMID: 33479248 |
Beyond Typical Ataxia Telangiectasia: How to Identify the Ataxia Telangiectasia-Like Disorders. | Raslan IR | Movement disorders clinical practice | 2020 | PMID: 33426167 |
Pathogenic Germline Mutations in Chinese Patients with Gastric Cancer Identified by Next-Generation Sequencing. | Zhou J | Oncology | 2020 | PMID: 32521533 |
Inherited DNA-Repair Defects in Colorectal Cancer. | AlDubayan SH | American journal of human genetics | 2018 | PMID: 29478780 |
Next-Generation Sequencing Reveals a Nonsense Mutation (p.Arg364Ter) in MRE11A Gene in an Indian Patient with Familial Breast Cancer. | Sharma Bhai P | Breast care (Basel, Switzerland) | 2017 | PMID: 28559769 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. | Maxwell KN | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25503501 |
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 |
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 |
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Text-mined citations for rs371077728 ...
HelpRecord last updated Jun 02, 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.