Variant classification summary

NM_005732.3:c.1110A>C

RAD50 · NP_005723.2:p.(Leu370Phe) · NM_005732.3

GRCh37: chr5:131924437 A>C · GRCh38: chr5:132588745 A>C

Gene: RAD50 Transcript: NM_005732.3

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

RAD50

Transcript

NM_005732.3

Protein

NP_005723.2:p.(Leu370Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Moderate): absent from gnomAD v2.1, v4.1, and gnomAD-Canada — AF = 0 across ~2 million alleles, below the <0.1% cutoff.

2

BP4 (Supporting): REVEL 0.131, BayesDel -0.441836, and SpliceAI max delta 0.01 are concordant for no impact.

3

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.

Final determination: Under the generic ACMG/AMP 2015 combination rules (Richards et al. 2015, PMID:25741868), the adjudicated combination of PM2 (moderate) + BP4 (supporting) — one pathogenic-direction moderate criterion with one benign-direction supporting criterion — meets no Pathogenic, Likely Pathogenic, Benign (BA1 alone or 2 BS), or Likely Benign (1 BS + 1 BP, or 2 BP) threshold; all other combinations are 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	Not applicable: as a missense substitution, the variant triggers no null-variant mechanism that PVS1 evaluates.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic record of p.Leu370Phe exists in ClinVar or the literature, so PS1 cannot be confirmed or ruled out.	clinvar pm5_candidates generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no maternity/paternity-confirmed de novo occurrence or family-history data exist for this variant.
PS3	Not assessed	Not assessed: no variant-specific functional study was available; in silico predictions cannot substitute for a functional assay.	oncokb spliceai revel bayesdel pvs1_gene_context generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-control or case-series data exist showing increased prevalence of this variant in affected individuals.	clinvar
PM1	Not assessed	Not assessed: no cancer-hotspot hit for RAD50 L370, and no curated domain annotation covers residue 370.	generic_acmg_combination_rules
PM2	Met	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 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no proband or phase data exist to establish the variant in trans with a pathogenic RAD50 allele.	clinvar generic_acmg_combination_rules pvs1_gene_context
PM4	N/A	Not applicable: missense substitution does not alter protein length, so there is nothing for PM4 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at residue 370 has an established pathogenic classification.	clinvar pm5_candidates generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no assumed-de novo evidence exists; no proband or parental-testing data are available.
PP1	Not assessed	Not assessed: no co-segregation data in affected family members exist for this variant.
PP2	Not assessed	Not assessed: no missense constraint data and no evidence that missense variants are a common RAD50 disease mechanism.	pvs1_gene_context generic_acmg_combination_rules
PP3	Not met	Not met: all computational evidence is concordant for no effect — SpliceAI max delta 0.01, REVEL 0.131, BayesDel -0.441836.	spliceai revel bayesdel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family-history data exist to evaluate phenotype specificity.	pvs1_gene_context
PP5	N/A	Not applicable: no ClinVar expert-panel pathogenic classification exists for this variant.	clinvar
BA1	Not met	Not met: allele frequency is 0% across gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% BA1 cutoff.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: allele frequency is 0%, far below the >0.3% BS1 cutoff for this rare recessive disorder.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: no healthy adult homozygote or carrier is documented — 0 alleles in all population datasets.	gnomad_v2 gnomad_v4 gnomad_canada clinvar generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no variant-specific functional study was available to show absence of a damaging effect.	oncokb spliceai revel bayesdel generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no non-segregation observations exist for this variant.
BP1	Not assessed	Not assessed: no mutation-spectrum data demonstrate that RAD50 disease is caused primarily by truncating variants.	pvs1_gene_context generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase or proband data exist to evaluate trans/cis configuration with a pathogenic allele.	clinvar generic_acmg_combination_rules pvs1_gene_context
BP3	N/A	Not applicable: missense substitution does not alter protein length within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL 0.131, BayesDel -0.441836, and SpliceAI max delta 0.01 are concordant for no impact.	revel bayesdel spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level data exist to confirm or exclude an alternative molecular diagnosis.
BP6	N/A	Not applicable: no ClinVar expert-panel benign classification exists for this variant.	clinvar
BP7	N/A	Not applicable: missense substitution alters the protein sequence, so the silent-variant premise does not apply.	generic_acmg_combination_rules

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.