Variant classification summary

NM_133509.4:c.585_587dupGGA

RAD51B · NP_598193.2:p.(Glu198dup) · NM_133509.4

GRCh37: chr14:68353749 T>TGGA · GRCh38: chr14:67887032 T>TGGA

Gene: RAD51B Transcript: NM_133509.4

Final call

VUS

PM2 supporting BP3 supporting

Variant details

Gene

RAD51B

Transcript

NM_133509.4

Protein

NP_598193.2:p.(Glu198dup)

gnomAD AF

1.998614294089431e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely low population frequency - maximum allele frequency 0.00190% (gnomAD v2.1), below the <0.1% threshold, with zero homozygotes.

2

BP3 (Supporting): in-frame duplication lengthens a poly-glutamate repeat tract without known function (p.Glu198dup, 384 to 385 amino acids), with no predicted splice impact (SpliceAI delta 0.01).

3

Final classification: Variant of Uncertain Significance - the one supporting pathogenic and one supporting benign criterion are conflicting and meet no combination threshold under generic ACMG/AMP 2015.

Final determination: Under generic ACMG/AMP 2015 combination rules (applied because no RAD51B VCEP/CSPEC framework exists), the only adjudicated criteria are PM2 (supporting) and BP3 (supporting); this conflicting 1-supporting-versus-1-supporting combination meets no Pathogenic, Likely Pathogenic, Benign, or Likely Benign threshold, 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	N/A	Not applicable: the in-frame duplication p.(Glu198dup) triggers no null-variant mechanism such as nonsense-mediated decay, so PVS1's premise does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: an in-frame duplication produces no altered amino acid residue to compare against a previously pathogenic missense change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing or de novo occurrence of this variant is documented in any clinical record.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional assay data exist for p.(Glu198dup); the only available signal was an in silico prediction, which does not qualify.	oncokb clinvar spliceai generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-control study of this variant exists; population allele frequencies alone cannot establish enrichment in affected individuals.	clinvar gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM1	N/A	Not applicable: the duplication creates no altered residue to evaluate for mutational hotspot or critical functional-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (supporting): the variant is extremely rare, with a maximum population allele frequency of 0.00190%, far below the <0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no genotype or phase data exist to show the variant is in trans with a pathogenic allele.	clinvar generic_acmg_combination_rules pvs1_gene_context gnomad_v2 gnomad_v4
PM4	Not met	Not met: although protein length changes (384 to 385 amino acids), the duplication lengthens a (GAA)3 repeat tract, and PM4 excludes repeat regions.	generic_acmg_combination_rules spliceai pvs1_variant_assessment gnomad_v2 gnomad_v4
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a different missense previously determined pathogenic.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo occurrence of this variant is reported in any proband or family record.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no segregation data exist - no affected relatives or informative meioses are reported for this variant.	clinvar generic_acmg_combination_rules
PP2	N/A	Not applicable: this is an in-frame duplication, not a missense change, so the gene's missense-constraint properties do not apply.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI predicts no splice impact (max delta 0.01 vs the 0.2 threshold), and no other calibrated computational evidence applies.	spliceai clinvar pvs1_variant_assessment generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history is available, and cancer predisposition is not a highly specific single-etiology phenotype.	generic_acmg_combination_rules pvs1_gene_context
PP5	N/A	Not applicable: no ClinVar expert panel has classified this exact variant pathogenic or likely pathogenic.	clinvar generic_acmg_combination_rules
BA1	Not met	Not met: the highest population allele frequency is 0.00190%, three orders of magnitude below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the highest population allele frequency is 0.00190%, far below the >0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: zero homozygotes in gnomAD (0 of ~1.5 million alleles), and the incompletely penetrant late-onset trait makes carrier status insufficient.	gnomad_v2 gnomad_v4 clinvar
BS3	Not assessed	Not assessed: no functional assay data exist for this variant; in silico splice predictions do not qualify as well-established functional studies.	oncokb clinvar spliceai generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no family genotyping exists to show that affected relatives do not carry the variant.	clinvar generic_acmg_combination_rules
BP1	N/A	Not applicable: this is an in-frame duplication, not a missense change, so the truncating-disease mechanism does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no genotype or phase data exist to place the variant in cis or trans with a pathogenic allele.	clinvar generic_acmg_combination_rules gnomad_v2 gnomad_v4
BP3	Met	Met (supporting): the in-frame p.Glu198dup lengthens a poly-glutamate repeat tract with no known function, with no predicted splice impact (SpliceAI delta 0.01).	generic_acmg_combination_rules spliceai pvs1_variant_assessment gnomad_v2 gnomad_v4
BP4	Not met	Not met: SpliceAI (delta 0.01) is the only computational line and addresses splicing only, while BP4 requires multiple lines of evidence.	spliceai clinvar pvs1_variant_assessment generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband genetic testing results are available to document an alternate molecular cause of disease.	generic_acmg_combination_rules
BP6	N/A	Not applicable: no ClinVar expert panel has classified this exact variant benign or likely benign.	clinvar generic_acmg_combination_rules
BP7	N/A	Not applicable: the duplication changes the protein sequence, so the synonymous-variant premise of BP7 does not hold.	generic_acmg_combination_rules

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