ClinVar Genomic variation as it relates to human health
NM_005591.4(MRE11):c.311G>C (p.Ser104Thr)
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.311G>C (p.Ser104Thr)
Variation ID: 127981 Accession: VCV000127981.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q21 11: 94485927 (GRCh38) [ NCBI UCSC ] 11: 94219093 (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 Jun 1, 2016 May 1, 2024 Aug 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005591.4:c.311G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005582.1:p.Ser104Thr missense NM_001330347.2:c.311G>C NP_001317276.1:p.Ser104Thr missense NM_005590.4:c.311G>C NP_005581.2:p.Ser104Thr missense NC_000011.10:g.94485927C>G NC_000011.9:g.94219093C>G NG_007261.1:g.12948G>C LRG_85:g.12948G>C LRG_85t1:c.311G>C LRG_85p1:p.Ser104Thr - Protein change
- S104T
- Other names
- p.S104T:AGT>ACT
- Canonical SPDI
- NC_000011.10:94485926:C:G
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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
The Genome Aggregation Database (gnomAD) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00019
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 |
2104 | 2140 |
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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 5, 2023 | RCV000115916.14 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 16, 2018 | RCV000212556.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 19, 2022 | RCV000684797.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 9, 2023 | RCV003129778.4 |
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
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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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Uncertain significance
(Mar 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000842795.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
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Uncertain significance
(Aug 09, 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: SCV004193818.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Feb 29, 2020)
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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: SCV003808917.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Sep 19, 2022)
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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: SCV000547395.6
First in ClinVar: Sep 24, 2016 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 104 of the MRE11 protein (p.Ser104Thr). … (more)
This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 104 of the MRE11 protein (p.Ser104Thr). This variant is present in population databases (rs587780140, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 31780696). ClinVar contains an entry for this variant (Variation ID: 127981). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Dec 12, 2013)
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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: SCV000149825.12
First in ClinVar: May 17, 2014 Last updated: Jun 01, 2016 |
Comment:
MRE11A, which is involved in DNA damage repair, has been only recently described in association with cancer predisposition and the risks are not well understood. … (more)
MRE11A, which is involved in DNA damage repair, has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted MRE11A c.311G>C at the cDNA level, p.Ser104Thr (S104T) at the protein level, and results in the change of a Serine to a Threonine (AGT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Ser104Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one neutral polar amino acid for another, altering a position that is well conserved throughout evolution and is located in the a2-b2 loop forming a H-bond that is involved in stabilizing the hMre11 core dimer (Park 2011). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the MRE11A gene, remain unclear. (less)
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Uncertain significance
(Aug 13, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002538420.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MRE11 c.311G>C (p.S104T) variant has been reported in heterozygosity in at least one individual with breast cancer (PMID: 31780696). This variant was observed in … (more)
The MRE11 c.311G>C (p.S104T) variant has been reported in heterozygosity in at least one individual with breast cancer (PMID: 31780696). This variant was observed in 2/35372 chromosomes in the Latino population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID: 127981). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The overall evidence is inconsistent with ACMG/AMP requirements for a classification of benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Jun 05, 2023)
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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: SCV000186540.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.S104T variant (also known as c.311G>C), located in coding exon 3 of the MRE11A gene, results from a G to C substitution at nucleotide … (more)
The p.S104T variant (also known as c.311G>C), located in coding exon 3 of the MRE11A gene, results from a G to C substitution at nucleotide position 311. The serine at codon 104 is replaced by threonine, an amino acid with similar properties. The p.S104 residue is located in the metallo-phosphatase domain and in involved in dimerization; the p.S104T alteration is anticipated to result in a decrease of dimerization, which is functionally critical (Ambry internal data, Seifert FU et al. Acta Crystallogr F Struct Biol Commun 2015 Jun;71(Pt 6):752-7). This alteration was identified in an individual diagnosed with breast cancer (Dutil J et al. Sci Rep, 2019 11;9:17769). 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)
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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 in cancer genes in high-risk non-BRCA patients from Puerto Rico. | Dutil J | Scientific reports | 2019 | PMID: 31780696 |
Structure of the catalytic domain of Mre11 from Chaetomium thermophilum. | Seifert FU | Acta crystallographica. Section F, Structural biology communications | 2015 | PMID: 26057807 |
Text-mined citations for rs587780140 ...
HelpRecord last updated May 08, 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.