Variant classification summary

NM_133509.4:c.171_173dupCAG

RAD51B · NP_598193.2:p.(Ser57dup) · NM_133509.4

GRCh37: chr14:68292263 T>TCAG · GRCh38: chr14:67825546 T>TCAG

Gene: RAD51B Transcript: NM_133509.4

Final call

Likely Benign

PM2 supporting BP3 supporting BP4 supporting

Variant details

Gene

RAD51B

Transcript

NM_133509.4

Protein

NP_598193.2:p.(Ser57dup)

gnomAD AF

6.200050840416892e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): present once in 1,612,890 gnomAD v4.1 alleles, indicating extreme rarity.

2

BP3 (Supporting): in-frame duplication of one CAG repeat unit in a tandem repeat region with no known function.

3

BP4 (Supporting): SpliceAI max delta 0.09, below the ~0.2 high-precision cutoff.

4

Likely Benign: under generic ACMG/AMP 2015 rules, the two supporting benign criteria outweigh the single supporting pathogenic criterion (PM2).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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 in-frame duplication is not a null variant, so no loss-of-function mechanism is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: no amino acid substitution exists to compare with a previously pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo observation or parental testing was available.
PS3	Not assessed	Not assessed: no functional assay data on this variant were available.
PS4	Not assessed	Not assessed: no case-control or prevalence data for this variant were available.
PM1	N/A	Not applicable: no altered residue exists to evaluate for a mutational hotspot.	generic_acmg_combination_rules
PM2	Met	Met (supporting): seen once in gnomAD v4.1 (1 in 1,612,890 alleles), indicating extreme rarity.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no biallelic or phase evidence was available.
PM4	Not met	Not met: the in-frame insertion lies within a tandem CAG repeat region, where BP3 applies instead.	clinvar pvs1_variant_assessment generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no documented de novo occurrence.
PP1	Not assessed	Not assessed: no familial segregation data were available.
PP2	N/A	Not applicable: no missense change exists to evaluate.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.09, below the ~0.2 high-precision threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype data were provided.
PP5	Not met	Not met: ClinVar reports only a single-submitter uncertain-significance record, not an expert-panel pathogenic classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 total frequency 6.2e-07, far below the 1% stand-alone benign threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest population frequency 0.013%, below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no homozygous carriers were observed.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional assay data on this variant were available.
BS4	Not assessed	Not assessed: no non-segregation evidence was available.
BP1	N/A	Not applicable: no missense change exists to evaluate.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no trans/cis phase information was available.
BP3	Met	Met (supporting): in-frame duplication of one CAG repeat unit in a tandem repeat region with no known function.	clinvar pvs1_variant_assessment generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.09, below the ~0.2 high-precision cutoff.	spliceai
BP5	Not assessed	Not assessed: no alternative molecular diagnosis was documented.
BP6	Not met	Not met: ClinVar reports only a single-submitter uncertain-significance record, not an expert-panel benign classification.	clinvar
BP7	N/A	Not applicable: the protein sequence is altered, so the synonymous-variant criterion 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.