Variant classification summary

NM_133509.4:c.82C>G

RAD51B · NP_598193.2:p.(Gln28Glu) · NM_133509.4

GRCh37: chr14:68290342 C>G · GRCh38: chr14:67823625 C>G

Gene: RAD51B Transcript: NM_133509.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RAD51B

Transcript

NM_133509.4

Protein

NP_598193.2:p.(Gln28Glu)

gnomAD AF

4.350155176249644e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD-Canada; maximum subgroup frequency 0.01653% and overall 0.000435%, both below the <0.1% threshold.

2

BP4 (Supporting): SpliceAI max delta 0.056 (below 0.2) and REVEL 0.071 predict no splice or missense impact.

3

VUS: one supporting pathogenic (PM2) and one supporting benign (BP4) criterion satisfies no Pathogenic or Benign combination under the generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 fallback: PM2(supporting) + BP4(supporting) does not meet any Pathogenic/Likely Pathogenic/Benign/Likely Benign combination threshold, so the call is 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: this missense substitution causes no null-variant mechanism, and PVS1 applies only to nonsense, frameshift, or splice-consensus variants.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: insufficient evidence was available to compare this variant against a known pathogenic change at the same amino acid position.
PS2	Not assessed	Not assessed: no parental genotypes, parentage confirmation, or de novo observation was available to establish de novo origin.
PS3	Not assessed	Not assessed: no validated functional assay data addressing this specific variant was available.
PS4	Not assessed	Not assessed: no case-control enrichment or affected-case series data was available for this variant.
PM1	Not assessed	Not assessed: insufficient evidence was available to evaluate location in a mutational hotspot or critical functional domain.
PM2	Met	Met (supporting): absent from gnomAD-Canada, with maximum subgroup frequency 0.01653% and overall 0.000435%, both below the <0.1% PM2 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no second-allele, phase, or inheritance data was available to evaluate a trans configuration.
PM4	N/A	Not applicable: this missense substitution causes no protein length change, which PM4 requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: insufficient evidence was available to identify an established pathogenic missense at the same amino acid position.
PM6	Not assessed	Not assessed: no unconfirmed de novo observation with negative family history was available.
PP1	Not assessed	Not assessed: no pedigree, affected relatives, or cosegregation data was available.
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate this gene's pattern of pathogenic missense variation.
PP3	Not met	Not met: SpliceAI max delta 0.056 is below the 0.2 splice-altering threshold and REVEL 0.071 predicts no missense impact.	spliceai revel
PP4	Not assessed	Not assessed: no sufficiently specific phenotype or genotype-phenotype correlation was available.
PP5	Not met	Not met: the exact variant is absent from ClinVar, with no expert-panel Pathogenic or Likely Pathogenic classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 total allele frequency is 0.000435%, far below the >1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: highest observed subgroup frequency is 0.01653%, below the >0.3% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no evidence of unaffected healthy adult carriers or healthy homozygotes was available.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay data showing a benign or wild-type-like effect for this variant was available.
BS4	Not assessed	Not assessed: no tested unaffected relatives or non-segregation evidence was available.
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate whether this missense variant meets BP1.
BP2	Not assessed	Not assessed: no second pathogenic variant, phase, or inheritance data was available to evaluate cis/trans configuration.
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel in a repetitive region, so BP3 does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.056 (below 0.2) and REVEL 0.071 (below pathogenic-supporting thresholds) predict no splice or missense impact.	spliceai revel
BP5	Not assessed	Not assessed: no alternative molecular etiology explaining the patient's phenotype was documented.
BP6	Not met	Not met: the exact variant is absent from ClinVar, with no expert-panel Benign or Likely Benign classification.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous variants, and this is a missense substitution.	generic_acmg_combination_rules

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