About MRE11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MRE11 c.1602G>T, p.(Glu534Asp)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
PM2 (supporting) is met: NM_005591.3:c.1602G>T is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes and genomes), and gnomAD-Canada v1.0. Population allele frequency is 0%, well below the 0.1% threshold for PM2 under generic ACMG.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
BP4 (supporting benign) is met: multiple lines of computational evidence predict no deleterious effect. REVEL score is 0.149 (well below 0.5). BayesDel score is -0.387603 (negative/benign). SpliceAI predicts no splice impact (max delta 0.02). All three independent in silico predictors are concordant in suggesting a neutral effect.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MRE11 is a tumor suppressor involved in DNA repair. Germline mutations of MRE11 are associated with ataxia-telangiectasia-like disorder and predispose
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 13 not met · 9 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005591.3:c.1602G>T (p.Glu534Asp) in MRE11 is a missense variant absent from gnomAD population databases (v2.1, v4.1, Canada).
The variant is absent from ClinVar and has not been reported in COSMIC or cancerhotspots.org.
Multiple in silico predictors (REVEL 0.149, BayesDel -0.387603, SpliceAI max delta 0.02) concordantly predict a neutral or benign effect.
No functional data, case-control data, segregation data, or de novo data are available for this variant.
Under generic ACMG/AMP 2015 rules, the only applicable criteria are PM2 (supporting pathogenic, absent from population databases) and BP4 (supporting benign, concordant benign in silico predictions).
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient to classify the variant. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingPM2 (supporting) is met: NM_005591.3:c.1602G>T is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes and genomes), and gnomAD-Canada v1.0. Population allele frequency is 0%, well below the 0.1% threshold for PM2 under generic ACMG. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes and genomes).
- Absent from gnomAD-Canada v1.0.
Sources
BP4 SupportingBP4 (supporting benign) is met: multiple lines of computational evidence predict no deleterious effect. REVEL score is 0.149 (well below 0.5). BayesDel score is -0.387603 (negative/benign). SpliceAI predicts no splice impact (max delta 0.02). All three independent in silico predictors are concordant in suggesting a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.149 (below pathogenic threshold of 0.5).
- BayesDel: -0.387603 (benign-leaning).
- SpliceAI max delta: 0.02 (no splice impact).
- Three concordant benign-leaning in silico predictions.
Sources
Not met · 13 · evaluated, threshold not reached
PS1 PS1 is not met: the variant p.Glu534Asp has not been previously reported as a pathogenic amino acid change in ClinVar or the literature. No established pathogenic variant at this residue with the same amino acid substitution exists. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no prior classification exists.
- No literature reports of the same amino acid change as pathogenic.
Sources
PS3 PS3 is not met: no variant-specific functional data or systematic range characterization (tiling screen, saturation mutagenesis, systematic truncation series) that includes residue E534 has been identified. OncoKB reports no variant-specific reviewed functional evidence, and no publications with functional data for this variant or the encompassing region were found. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional evidence.
- No functional studies identified in literature search.
- No systematic range characterization (tiling screen
- saturation mutagenesis) available for this region.
Still missing
- No functional studies available for p.Glu534Asp or a systematically characterized range that includes E534.
Sources
PM1 PM1 is not met: position E534 does not lie within a statistically significant cancerhotspots.org hotspot, and no well-characterized critical functional domain with direct disease evidence has been identified for this specific residue. Although MRE11 is a DNA repair protein with known functional domains, the C-terminal region (∼residue 534) lacks specific domain-level evidence sufficient to qualify for PM1 under generic ACMG. Details ▾Hide ▴
Evidence considered
- Not located in a significant cancerhotspots.org mutational hotspot.
- No ClinVar clustering of pathogenic variants at this residue.
- MRE11 nuclease and DNA-binding domains are characterized
- but residue E534 lies outside a well-defined disease-critical functional domain.
Still missing
- No published functional domain characterization that specifically implicates the E534 region in disease.
Sources
PM5 PM5 is not met: no alternate pathogenic missense variant at the same amino acid residue (E534) has been identified in ClinVar. PM5 candidate search returned zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- Zero same-residue candidates found in ClinVar.
- PM5 candidate harvesting system found no comparator variants at residue E534.
Still missing
- No pathogenic missense variants at codon 534 identified in any database.
Sources
clinvar ↗pm5_candidates
PP3 PP3 is not met: in silico predictors uniformly indicate a benign effect. REVEL score is 0.149 (well below the pathogenic threshold of 0.5). BayesDel score is -0.387603 (negative; benign-leaning). SpliceAI predicts no significant splice impact (max delta score 0.02). Multiple lines of computational evidence support a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.149 (below 0.5 pathogenic threshold).
- BayesDel score: -0.387603 (benign-leaning).
- SpliceAI max delta score: 0.02 (no predicted splice impact).
Sources
PP5 PP5 is not met: the variant is absent from ClinVar. There is no expert panel or multi-submitter classification to support a pathogenic interpretation. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no classification or review status exists.
Sources
BA1 BA1 is not met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Population allele frequency is 0%, well below the 1% threshold. Details ▾Hide ▴
Evidence considered
- Variant is absent from all population databases (AF = 0%).
Sources
BS1 BS1 is not met: the variant is absent from all population databases with an allele frequency of 0%, which does not exceed the 0.3% threshold required for BS1. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD (AF = 0%)
- not meeting the >0.3% threshold.
Sources
BS2 BS2 is not met: the variant has not been observed in any healthy adult individual in gnomAD or other population databases. Absence from databases does not satisfy the requirement for observation in a healthy adult. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD
- no healthy adult observations exist.
Sources
BS3 BS3 is not met: no functional studies demonstrating a benign or neutral effect for p.Glu534Asp or the region encompassing residue E534 have been identified. While in silico predictors are benign-leaning (REVEL 0.149, BayesDel -0.387603), these are computational predictions, not experimental functional data, and do not qualify for BS3. Details ▾Hide ▴
Evidence considered
- No experimental functional studies demonstrating a benign effect exist.
- REVEL (0.149) and BayesDel (-0.387603) are computational predictors
- not functional data.
Still missing
- No functional assay data demonstrating normal protein function for this variant.
Sources
revelbayesdel
BP1 BP1 is not met: although MRE11 has an established loss-of-function disease mechanism, pathogenic missense variants are also well-described in MRE11-associated disorders (ataxia-telangiectasia-like disorder and cancer predisposition). The gene does not cause disease predominantly through truncating variants alone, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- MRE11 LoF mechanism is established but pathogenic missense variants are also well-documented.
- BP1 requires the gene to cause disease predominantly through truncating variants
- which is not the case for MRE11.
Sources
pvs1_gene_context
BP6 BP6 is not met: the variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no classification or review status exists.
Sources
PS5 PS5 is not met: no previously established pathogenic missense variant at amino acid residue E534 has been identified in ClinVar. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar.
- PM5 candidate search found zero same-residue comparator variants.
- No prior disease-associated variant at E534 exists.
Sources
clinvar ↗pm5_candidates
Not assessed · 9 · no assessment recorded
PS2 PS2 cannot be assessed: no parental testing or de novo data are available for this case. Details ▾Hide ▴
Still missing
- No family data or de novo testing results available.
PS4 PS4 cannot be assessed: no case-control data or prevalence statistics in affected individuals are available for this variant. The variant is absent from gnomAD but no affected-patient cohort data exist. Details ▾Hide ▴
Still missing
- No case-control or affected-population prevalence data available.
PM6 PM6 cannot be assessed: no de novo data or parental confirmation testing results are available for this case. Details ▾Hide ▴
Still missing
- No de novo testing data available.
PP1 PP1 cannot be assessed: no family segregation data are available for this case. Details ▾Hide ▴
Still missing
- No cosegregation or family history data available.
PP2 PP2 cannot be assessed: MRE11 is not included in the HCI prior gene set, so missense constraint (z-score) data are unavailable. Without a quantitative measure of selective constraint against missense variation in this gene, PP2 cannot be evaluated. Details ▾Hide ▴
Evidence considered
- HCI prior not available for MRE11 (gene_not_supported).
- No alternative missense constraint metric (e.g.
- gnomAD missense z-score) available for assessment.
Still missing
- No missense constraint data available for MRE11.
PP4 PP4 cannot be assessed: no patient phenotype information is available for this case to evaluate specificity of presentation for MRE11-related disease. Details ▾Hide ▴
Still missing
- No patient phenotype data available.
BS4 BS4 cannot be assessed: no family segregation data are available to evaluate lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No family or segregation data available.
BP2 BP2 cannot be assessed: no phasing data are available to determine whether this variant is observed in trans with a pathogenic variant. Details ▾Hide ▴
Still missing
- No phasing or in trans data available.
BP5 BP5 cannot be assessed: no alternative molecular basis for disease has been identified in this case, and no case-specific clinical data are available for review. Details ▾Hide ▴
Still missing
- No case-level data to evaluate alternative molecular etiology.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_005591.3:c.1602G>T is a missense variant (p.Glu534Asp) that does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution (G>T)
- not a predicted null variant.
- Generic PVS1 framework (PMC6185798) requires a null-variant mechanism
- this missense does not qualify.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/ABP7 is not applicable: NM_005591.3:c.1602G>T is a missense variant (p.Glu534Asp), not a synonymous variant with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not synonymous.
- BP7 applies only to synonymous variants without splice effect.
Identifiers
- Gene
- MRE11
- Transcript
- NM_005591.3
- Coding (HGVS c.)
- NM_005591.3:c.1602G>T
- Protein (HGVS p.)
- NP_005582.1:p.(Glu534Asp)
- GRCh38
- chr11:94447400 C>A
- GRCh37
- chr11:94180566 C>A
Gene diagram
Every interpreted variant in MRE11, mapped onto the exon structure of NM_005591.3. Select a row to find it on the plot.
MRE11NM_005591.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MRE11
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.149
- BayesDel
- -0.388
How the predictions were used
BP4 SupportingBP4 (supporting benign) is met: multiple lines of computational evidence predict no deleterious effect. REVEL score is 0.149 (well below 0.5). BayesDel score is -0.387603 (negative/benign). SpliceAI predicts no splice impact (max delta 0.02). All three independent in silico predictors are concordant in suggesting a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.149 (below pathogenic threshold of 0.5).
- BayesDel: -0.387603 (benign-leaning).
- SpliceAI max delta: 0.02 (no splice impact).
- Three concordant benign-leaning in silico predictions.
Sources
PP3 PP3 is not met: in silico predictors uniformly indicate a benign effect. REVEL score is 0.149 (well below the pathogenic threshold of 0.5). BayesDel score is -0.387603 (negative; benign-leaning). SpliceAI predicts no significant splice impact (max delta score 0.02). Multiple lines of computational evidence support a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.149 (below 0.5 pathogenic threshold).
- BayesDel score: -0.387603 (benign-leaning).
- SpliceAI max delta score: 0.02 (no predicted splice impact).
Sources
BP7 N/ABP7 is not applicable: NM_005591.3:c.1602G>T is a missense variant (p.Glu534Asp), not a synonymous variant with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not synonymous.
- BP7 applies only to synonymous variants without splice effect.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.149. BayesDel score = -0.387603.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_005591.3%3Ac.1602G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-94180566-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-94447400-C-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-94447400-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005591.3%3Ac.1602…
- OncoKB ↗www.oncokb.org/gene/MRE11/E534D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MRE11+c.1602G%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.149. BayesDel score = -0.387603.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MRE11 is a tumor suppressor involved in DNA repair. Germline mutations of MRE11 are associated with ataxia-telangiectasia-like disorder and predispose
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.