NM_005591.3:c.1444C>T

MRE11 · NP_005582.1:p.(Gln482Ter) · NM_005591.3

GRCh37: chr11:94192630 G>A · GRCh38: chr11:94459464 G>A

Gene: MRE11 Transcript: NM_005591.3

Final call

VUS

PVS1 strong PM2 supporting

Variant details

Gene

MRE11

Transcript

NM_005591.3

Protein

NP_005582.1:p.(Gln482Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005591.3:c.1444C>T produces a premature termination codon (p.Gln482Ter) in exon 13 of 20 of MRE11 with predicted nonsense-mediated decay, meeting PVS1 at strong strength.

This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.

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	Met	NM_005591.3:c.1444C>T is a nonsense variant producing p.(Gln482Ter) in exon 13 of 20. NMD is predicted (c.1444 is 627 nt upstream of the last exon-exon junction). This removes the C-terminal DNA-binding domains and GAR motif. MRE11 loss-of-function is an established disease mechanism for ataxia-telangiectasia-like disorder (ATLD) and heterozygous cancer predisposition. Under PMC6185798, a nonsense variant with predicted NMD in a gene where LoF is a known mechanism qualifies for PVS1 at strong level.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies when the same amino acid change arises from a different nucleotide change and is established as pathogenic. No alternative nucleotide change producing p.Q482* (e.g., c.1444C>A) has been identified in ClinVar or the literature. Not applicable.
PS2	Not met	No de novo observation data are available for this variant. PS2 requires confirmed de novo occurrence with maternity and paternity confirmed.
PS3	Not met	No functional studies were identified that directly tested NM_005591.3:c.1444C>T (p.Q482*) or that systematically characterized a range spanning this position. Four high-priority functional papers on MRE11 were reviewed; none examined this specific variant. Domain-level inference from nearby studies does not satisfy PS3's requirement for variant-specific or systematic-range functional evidence.
PS4	Not met	No case-control or prevalence data are available for this variant. The variant is absent from ClinVar, and no publications report affected individuals carrying this variant.
PS5	Not met	No evidence of this variant occurring in trans with a known pathogenic MRE11 variant. PS5 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
PM1	Not met	PM1 is most informative for missense variants in critical domains. For this truncating variant, the loss of the entire C-terminal region is already captured by PVS1. No residue-specific hotspot was identified at Q482 by cancerhotspots.org, and the domain-level argument is coextensive with the PVS1 assessment. Applying PM1 in addition to PVS1 would constitute double-counting of the same loss-of-function evidence.
PM2	Met	This variant is absent from all population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Under non-VCEP ACMG rules, a variant absent from or present at <0.1% in large population cohorts meets PM2 at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	PM5 requires a different pathogenic missense change at the same residue (Q482). No pathogenic missense variants at codon 482 were identified in ClinVar. The pm5_candidates search found zero same-residue comparator candidates. The variant creates a premature stop codon, and no alternative pathogenic missense substitution has been reported at this position.	pm5_candidates clinvar
PM6	Not met	No de novo observation data are available for this variant. PM6 requires a de novo observation without confirmation of maternity and paternity.
PP1	Not met	No segregation data are available for this variant in affected families.
PP2	N/A	PP2 applies to missense variants in genes with low rates of benign missense variation. This variant is a nonsense (stop-gain) variant, not a missense substitution.
PP3	N/A	PP3 evaluates in silico predictions for missense or splice-affecting variants. For this nonsense variant with predicted NMD, the deleterious effect is inherent in the stop codon and NMD mechanism, which is already assessed under PVS1. SpliceAI predicts no splice impact (max delta 0.01), confirming no cryptic splice effect. Applying PP3 in addition to PVS1 would constitute double-counting of the same deleterious effect.	spliceai bayesdel
PP4	Not met	No patient phenotype data are available for this variant. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5	Not met	This variant is absent from ClinVar and has not been reported as pathogenic or likely pathogenic by any reputable source.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the 1% BA1 threshold (non-VCEP).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the 0.3% BS1 threshold (non-VCEP).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available regarding observation of this variant in healthy adult individuals. The variant is absent from population databases, so healthy carrier status cannot be assessed.
BS3	Not met	No functional studies have been performed on this specific variant that would demonstrate no deleterious effect. The four functional MRE11 papers reviewed did not test p.Q482*.
BS4	Not met	No family segregation data are available to demonstrate lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where a truncating mechanism is the primary cause of disease. This variant is a nonsense (truncating) variant, not a missense substitution.
BP2	Not met	No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4	N/A	BP4 evaluates in silico predictions suggesting no impact on the gene product. For this nonsense variant with predicted NMD, the deleterious impact is inherent in the premature stop codon. SpliceAI delta 0.01 indicates no cryptic splice effect, but this does not constitute evidence of benign impact. BP4 is not applicable to nonsense variants with a clear NMD-based loss-of-function mechanism.
BP5	Not met	No alternate molecular basis for disease has been identified in a case harboring this variant.
BP6	Not met	This variant is absent from ClinVar and has not been reported as benign or likely benign by any reputable source.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense (stop-gain) substitution, not a synonymous change.

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