Classification rationale

PM2 BP4 VUS

MRE11 c.1602G>T

NM_005591.3:c.1602G>T (p.Glu534Asp) in MRE11 is a missense variant absent from gnomAD population databases (v2.1, v4.1, Canada).¹ The variant is absent from ClinVar and has not been reported in COSMIC or cancerhotspots.org.² Multiple in silico predictors (REVEL 0.149, BayesDel -0.387603, SpliceAI max delta 0.02) concordantly predict a neutral or benign effect.³ 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).⁴ 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).⁵

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 clinvar ↗

3 revelbayesdelspliceai ↗

4 generic_acmg_combination_rules

5 generic_acmg_combination_rules

Gene diagram · NM_005591.3 · variants mapped to exon structure

MRE11 NM_005591.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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.

Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes and genomes).Absent from gnomAD-Canada v1.0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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.

REVEL: 0.149 (below pathogenic threshold of 0.5).BayesDel: -0.387603 (benign-leaning).SpliceAI max delta: 0.02 (no splice impact).

spliceai ↗

Assessed · not applied

Pathogenic

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.

PS2 PS2 cannot be assessed: no parental testing or de novo data are available for this case.

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.

PS4 PS4 cannot be assessed: no case-control data or prevalence statistics in affected individuals are available for this variant.

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.

PM5 PM5 is not met: no alternate pathogenic missense variant at the same amino acid residue (E534) has been identified in ClinVar.

PM6 PM6 cannot be assessed: no de novo data or parental confirmation testing results are available for this case.

PP1 PP1 cannot be assessed: no family segregation data are available for this case.

PP2 PP2 cannot be assessed: MRE11 is not included in the HCI prior gene set, so missense constraint (z-score) data are unavailable.

PP3 PP3 is not met: in silico predictors uniformly indicate a benign effect.

PP4 PP4 cannot be assessed: no patient phenotype information is available for this case to evaluate specificity of presentation for MRE11-related disease.

PP5 PP5 is not met: the variant is absent from ClinVar.

Benign

BA1 BA1 is not met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

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.

BS2 BS2 is not met: the variant has not been observed in any healthy adult individual in gnomAD or other population databases.

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.

BS4 BS4 cannot be assessed: no family segregation data are available to evaluate lack of cosegregation with disease.

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).

BP2 BP2 cannot be assessed: no phasing data are available to determine whether this variant is observed in trans with a pathogenic variant.

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.

BP6 BP6 is not met: the variant is absent from ClinVar.

N/A · 2 PVS1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

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.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots