MRE11c.1444C>TUncertain significance

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Variant interpretation report

MRE11 c.1444C>T, p.(Gln482Ter)

NM_005591.3:c.1444C>T NP_005582.1:p.(Gln482Ter) View identifiers

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.

About MRE11

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 10 Jul 2026 · version 7.0.3

Evidence considered

View criteria

Applied evidence criteria

PVS1 (strong): 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.
PM2 (supporting): 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.

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: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Strong

PVS1 · strong

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.

PM2Supporting

PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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: PVS1 strong, PM2 supporting; combination = 1 strong + 1 supporting, 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.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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

COSMIC ↗Cancer Hotspots ↗

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 · 18 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

Met · 2

PVS1 StrongNM_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. Details ▾Hide ▴

Evidence considered

Nonsense variant p.Q482* in exon 13 of 20 with predicted NMD.
MRE11 loss-of-function is established as a germline disease mechanism (ATLD
heterozygous cancer predisposition reported in PMID:40072281 and others).
Under PMC6185798
nonsense variants with NMD in LoF-established genes meet PVS1 at strong strength.

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM2 SupportingThis 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. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (0 alleles).
Absent from gnomAD v4.1 (0 alleles).
Absent from gnomAD-Canada v1.0 (0 alleles).

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 18 · evaluated, threshold not reached

PS2 No de novo observation data are available for this variant. PS2 requires confirmed de novo occurrence with maternity and paternity confirmed. Details ▾Hide ▴

Still missing

No trio or de novo testing data available.

PS3 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. Details ▾Hide ▴

Evidence considered

Four functional publications on MRE11 reviewed (PMID:23912341
PMID:24927325
PMID:28436950
PMID:33558481)
none tested this specific variant.

Still missing

No variant-specific functional data exist for p.Q482*.

PS4 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. Details ▾Hide ▴

Still missing

No case reports or cohort studies including this variant.

PM1 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. Details ▾Hide ▴

Evidence considered

Cancerhotspots.org did not identify Q482 as a statistically significant hotspot residue.
The truncation removes C-terminal DNA-binding domains and GAR motif but this is the same evidence supporting PVS1.

PM5 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. Details ▾Hide ▴

Evidence considered

No pathogenic missense variants at codon 482 identified in ClinVar.
PM5 candidate harvesting found zero candidates.

Sources

pm5_candidatesclinvar ↗

PM6 No de novo observation data are available for this variant. PM6 requires a de novo observation without confirmation of maternity and paternity. Details ▾Hide ▴

Still missing

No de novo data available.

PP1 No segregation data are available for this variant in affected families. Details ▾Hide ▴

Still missing

No family segregation data available.

PP4 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. Details ▾Hide ▴

Still missing

No clinical phenotype data available for carriers of this variant.

PP5 This variant is absent from ClinVar and has not been reported as pathogenic or likely pathogenic by any reputable source. Details ▾Hide ▴

Evidence considered

Variant is absent from ClinVar
no classification from any submitter.

Sources

clinvar ↗

BA1 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). Details ▾Hide ▴

Evidence considered

Absent from all gnomAD datasets (allele frequency = 0.0% in all populations).

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 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). Details ▾Hide ▴

Evidence considered

Absent from all gnomAD datasets (allele frequency = 0.0% in all populations).

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS2 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. Details ▾Hide ▴

Still missing

No data on healthy carriers.

BS3 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*. Details ▾Hide ▴

Evidence considered

No variant-specific functional studies identified.

Still missing

No functional data for this variant.

BS4 No family segregation data are available to demonstrate lack of segregation with disease. Details ▾Hide ▴

Still missing

No segregation data available.

BP2 No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴

Still missing

No trans-phase data available.

BP5 No alternate molecular basis for disease has been identified in a case harboring this variant. Details ▾Hide ▴

Still missing

No case data with alternative molecular diagnosis available.

BP6 This variant is absent from ClinVar and has not been reported as benign or likely benign by any reputable source. Details ▾Hide ▴

Evidence considered

Variant is absent from ClinVar
no classification from any submitter.

Sources

clinvar ↗

PS5 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. Details ▾Hide ▴

Still missing

No trans-phase data available.

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.01 (no splice impact).
BayesDel score = 0.653 (deleterious prediction
but not independently informative for a nonsense variant with predicted NMD).

Sources

spliceai ↗bayesdel

BP1 N/ABP1 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. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 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. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense (stop-gain) substitution, not a synonymous change. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: MRE11
Transcript: NM_005591.3
Coding (HGVS c.): NM_005591.3:c.1444C>T
Protein (HGVS p.): NP_005582.1:p.(Gln482Ter)
GRCh38: chr11:94459464 G>A
GRCh37: chr11:94192630 G>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 — 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

SpliceAI acceptor lossat +134 bp

0.010

SpliceAI acceptor gainat +440 bp

0.000

SpliceAI donor lossat +208 bp

0.000

SpliceAI donor gainat -60 bp

0.000

Pangolin splice lossmagnitude shown

-0.020

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: 0.653

How the predictions were used

Evidence considered

SpliceAI max delta score = 0.01 (no splice impact).
BayesDel score = 0.653 (deleterious prediction
but not independently informative for a nonsense variant with predicted NMD).

Sources

spliceai ↗bayesdel

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense (stop-gain) substitution, not a synonymous change. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.652534.

4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms.

Characterizes functional impact of four disease-associated MRE11 mutants (ATLD1, ATLD17/W243R, ASM/ΔD340-366, GRM/R572Q) on ATM/ATR signaling and MRN complex stability using murine cell lines. Demonstrates that N-terminal MRE11 mutations abrogate NBS1 binding and ATM activation, while C-terminal truncation ATLD1 maintains MRN interactions but reduces protein levels.
Does not name this variant
PMID 23912341 ↗
Quoted passage
MRE11AATLD1 contains a nonsense mutation that truncates 76 amino acid residues from the MRE11 C-terminus.
Results (Figures 3-8); Discussion
Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro.

Evaluates MRE11/RAD50/NBS1 complex protein expression loss in endometrial cancers and PARP-inhibitor sensitivity. Reports a recurrent intronic poly(T) mutation hotspot in MRE11 in microsatellite-instable endometrial cancers, not germline variants.
Does not name this variant
PMID 24927325 ↗
Quoted passage
One of the most common recurrent mutation is found in the MRE11 gene, whose product is a part of the MRE11-RAD50-NBS1 (MRN)-complex that is involved in the detection and repair of DNA double-strand breaks (DSBs).
Introduction; Results
MRE11 stability is regulated by CK2-dependent interaction with R2TP complex.

Demonstrates that MRE11 directly interacts with the R2TP chaperone complex subunit PIH1D1 via CK2-dependent phosphorylation, regulating MRE11 protein stability. Identifies C-terminal MRE11 truncations (including the ATLD1 R633* mutant) as relevant to protein stability.
Does not name this variant
PMID 28436950 ↗
Quoted passage
The MRE11 C-terminal part contains two potential DNA-binding domains and a glycine-arginine-rich motif, involved in the regulation of MRE11 nuclease activity and DNA binding.
Introduction
SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells.

Identifies SPRTN as the protease that cleaves MRE11 at residues 559-580 to produce a C-terminally truncated form (TR-MRE11) with impaired nuclease activity and DNA repair. TR-MRE11 lacks DNA-binding capacity but retains RAD50/NBS1 interaction.
Does not name this variant
PMID 33558481 ↗
Quoted passage
the SPRTN-dependent cleavage site for MRE11 was identified between 559 and 580 amino acids.
Abstract; Results

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 0.010 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

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 = 0.01). BayesDel score = 0.652534.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.