Variant classification summary

NM_002878.4:c.355T>C

RAD51D · NP_002869.3:p.(Cys119Arg) · NM_002878.4

GRCh37: chr17:33434132 A>G · GRCh38: chr17:35107113 A>G

Gene: RAD51D Transcript: NM_002878.4

Final call

VUS

BP4 supporting

Variant details

Gene

RAD51D

Transcript

NM_002878.4

Protein

NP_002869.3:p.(Cys119Arg)

gnomAD AF

0.00013569008632120013 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP4 supporting is met because missense REVEL 0.219 is below the generic <=0.29 threshold.

Final determination: Under generic ACMG/AMP 2015 rules, one supporting benign criterion does not meet a benign or likely benign threshold, so the variant is classified as VUS.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: p.Cys119Arg was reported as most likely benign, with no established pathogenic variant producing the same amino-acid change identified.	PMID:22415235 clinvar
PS2	Not assessed	Not assessed: the report identifies the variant in one Belgian family but provides no maternity, paternity, or de novo testing result.	PMID:22415235
PS3	Not assessed	Not assessed: the exact variant has only computational observations, with no validated functional assay demonstrating a damaging effect.	PMID:22415235 PMID:24130102
PS4	Not assessed	Not assessed: exact-variant case reports lack a matched control comparison and variant-specific OR/RR with a 95% confidence interval.	PMID:22415235 PMID:24130102 PMID:26261251
PM1	Not assessed	Not assessed: Cancer Hotspots found no RAD51D C119 hotspot, but no authoritative critical-domain annotation establishes whether residue 119 meets PM1.	hotspots cosmic
PM2	Not met	Not met: gnomAD v4.1 all-comers AF is 0.00013569, above the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: the variant was reported in a family, but no pathogenic second allele or parental/offspring phase testing establishes a PM3 observation.	PMID:22415235
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no established pathogenic alternate missense at Cys119 was identified, but comprehensive same-residue review is unavailable.	pm5_candidates PMID:22415235 clinvar
PM6	Not assessed	Not assessed: the report identifies the variant in one Belgian family but provides no evidence of assumed de novo occurrence or parental testing.	PMID:22415235
PP1	Not assessed	Not assessed: the report identifies the variant in a Belgian family but provides no affected-relative genotypes, cosegregation data, or informative meioses.	PMID:22415235
PP2	Not assessed	Not assessed: the case lacks a gene-wide benign-missense rate and evidence that missense variants are a common RAD51D disease mechanism.	gnomad_v4 PMID:26689913
PP3	Not met	Not met: missense REVEL 0.219 is below the generic PP3 supporting threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: the available records do not document a phenotype or family history highly specific for a single-gene disease.	PMID:22415235 PMID:24130102
PP5	Not met	Not met: ClinVar has zero expert-panel submissions and no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.0001554, well below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.0001554, below the generic 0.01 BS1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD has one homozygote, but no verified healthy-adult phenotype or early-age full-penetrance evidence is available.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: computationally benign predictions do not demonstrate experimentally that p.Cys119Arg has no damaging effect on protein function or splicing.	PMID:22415235 PMID:24130102
BS4	Not assessed	Not assessed: the report provides no genotypes or disease-status comparisons for affected relatives, so lack of segregation cannot be established.	PMID:22415235
BP1	Not assessed	Not assessed: RAD51D truncating variants are disease-relevant, but a primarily truncating disease mechanism is not established by the available evidence.	PMID:26689913
BP2	Not assessed	Not assessed: no pathogenic second variant or phase result shows the evaluated variant in trans or cis as required for BP2.	PMID:22415235
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting: missense REVEL 0.219 meets the generic BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no exact-variant case is documented with an alternate molecular basis for the disease.	PMID:22415235 PMID:24130102
BP6	Not met	Not met: ClinVar's Likely benign assertions are non-expert submissions, and the exact-variant record has no expert-panel classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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