Classification rationale

PM2 BP4 VUS

RAD50 c.1110A>C

PM2 (Moderate): absent from gnomAD v2.1, v4.1, and gnomAD-Canada — AF = 0 across ~2 million alleles, below the <0.1% cutoff. BP4 (Supporting): REVEL 0.131, BayesDel -0.441836, and SpliceAI max delta 0.01 are concordant for no impact. Final: Variant of Uncertain Significance — the conflicting 1 moderate (PM2) + 1 supporting (BP4) combination meets no Pathogenic, Likely Pathogenic, Benign, or Likely Benign threshold under generic ACMG/AMP 2015.

PM2 + BP4 → VUS

Gene diagram · NM_005732.3 · variants mapped to exon structure

RAD50 NM_005732.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate Pathogenic

Met (moderate): absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF = 0 across ~2 million alleles), below the <0.1% cutoff.

gnomad_v2: variant absent (0/125,748 exomes), 0 homozygotesgnomad_v4: variant absent (0/~1.6M alleles), 0 homozygotesgnomad_canada: variant absent from gnomAD-Canada v1.0 (HostSeq genomes)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (supporting): REVEL 0.131, BayesDel -0.441836, and SpliceAI max delta 0.01 are concordant for no impact.

REVEL score 0.131 - low, benign-range missense predictionBayesDel noAF score -0.441836 - negative, benign-range missense predictionSpliceAI max delta score 0.01 (DS_AL 0.01; DS_AG/DS_DG/DS_DL 0.0) - no splice impact predicted

spliceai ↗

Assessed · not applied

Pathogenic

PS1 Not assessed: no established pathogenic record of p.Leu370Phe exists in ClinVar or the literature, so PS1 cannot be confirmed or ruled out.

PS2 Not assessed: no maternity/paternity-confirmed de novo occurrence or family-history data exist for this variant.

PS3 Not assessed: no variant-specific functional study was available; in silico predictions cannot substitute for a functional assay.

PS4 Not assessed: no case-control or case-series data exist showing increased prevalence of this variant in affected individuals.

PM1 Not assessed: no cancer-hotspot hit for RAD50 L370, and no curated domain annotation covers residue 370.

PM3 Not assessed: no proband or phase data exist to establish the variant in trans with a pathogenic RAD50 allele.

PM5 Not assessed: no different missense change at residue 370 has an established pathogenic classification.

PM6 Not assessed: no assumed-de novo evidence exists; no proband or parental-testing data are available.

PP1 Not assessed: no co-segregation data in affected family members exist for this variant.

PP2 Not assessed: no missense constraint data and no evidence that missense variants are a common RAD50 disease mechanism.

PP3 Not met: all computational evidence is concordant for no effect — SpliceAI max delta 0.01, REVEL 0.131, BayesDel -0.441836.

PP4 Not assessed: no proband phenotype or family-history data exist to evaluate phenotype specificity.

Benign

BA1 Not met: allele frequency is 0% across gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% BA1 cutoff.

BS1 Not met: allele frequency is 0%, far below the >0.3% BS1 cutoff for this rare recessive disorder.

BS2 Not met: no healthy adult homozygote or carrier is documented — 0 alleles in all population datasets.

BS3 Not assessed: no variant-specific functional study was available to show absence of a damaging effect.

BS4 Not assessed: no non-segregation observations exist for this variant.

BP1 Not assessed: no mutation-spectrum data demonstrate that RAD50 disease is caused primarily by truncating variants.

BP2 Not assessed: no phase or proband data exist to evaluate trans/cis configuration with a pathogenic allele.

BP5 Not assessed: no proband-level data exist to confirm or exclude an alternative molecular diagnosis.

N/A · 6 PVS1 · PM4 · PP5 · BP3 · BP6 · 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 = 0.01). REVEL score = 0.131. BayesDel score = -0.441836.

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. RAD50 encodes a component of protein complex critical to DNA double-stranded-break end processing. Select germline mutations of RAD50 predispose to br

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