NM_005591.3:c.1602G>T

MRE11 · NP_005582.1:p.(Glu534Asp) · NM_005591.3

GRCh37: chr11:94180566 C>A · GRCh38: chr11:94447400 C>A

Gene: MRE11 Transcript: NM_005591.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MRE11

Transcript

NM_005591.3

Protein

NP_005582.1:p.(Glu534Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 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.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	clinvar
PS2	Not assessed	PS2 cannot be assessed: no parental testing or de novo data are available for this case.
PS3	Not met	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.	oncokb
PS4	Not assessed	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.
PS5	Not met	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.	clinvar pm5_candidates
PM1	Not met	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.	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	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.	clinvar pm5_candidates
PM6	Not assessed	PM6 cannot be assessed: no de novo data or parental confirmation testing results are available for this case.
PP1	Not assessed	PP1 cannot be assessed: no family segregation data are available for this case.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	PP4 cannot be assessed: no patient phenotype information is available for this case to evaluate specificity of presentation for MRE11-related disease.
PP5	Not met	PP5 is not met: the variant is absent from ClinVar. There is no expert panel or multi-submitter classification to support a pathogenic interpretation.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.	revel bayesdel
BS4	Not assessed	BS4 cannot be assessed: no family segregation data are available to evaluate lack of cosegregation with disease.
BP1	Not met	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.	pvs1_gene_context
BP2	Not assessed	BP2 cannot be assessed: no phasing data are available to determine whether this variant is observed in trans with a pathogenic variant.
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	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	Not met	BP6 is not met: the variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	BP7 is not applicable: NM_005591.3:c.1602G>T is a missense variant (p.Glu534Asp), not a synonymous variant with no predicted splice impact.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.