Variant classification summary

NM_002878.4:c.715C>T

RAD51D · NP_002869.3:p.(Arg239Trp) · NM_002878.4

GRCh37: chr17:33430296 G>A · GRCh38: chr17:35103277 G>A

Gene: RAD51D Transcript: NM_002878.4

Final call

Likely Benign

BP1 supporting BP4 supporting BP5 supporting

Variant details

Gene

RAD51D

Transcript

NM_002878.4

Protein

NP_002869.3:p.(Arg239Trp)

gnomAD AF

1.9863266241013424e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP1 supporting: RAD51D disease evidence is predominantly loss-of-function while the target is missense.

2

BP4 supporting: the missense REVEL score of 0.287 meets the <=0.29 threshold.

3

BP5 supporting: the variant repeatedly co-occurred with pathogenic RAD51D c.694C>T, providing an alternate molecular basis for reported disease.

Final determination: Under the generic ACMG/AMP 2015 fallback, at least two supporting benign criteria support a Likely Benign classification; BP1, BP4, and BP5 are present at supporting strength.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002878.4:c.715C>T in RAD51D is a missense substitution predicted to produce NP_002869.3:p.(Arg239Trp). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no independent pathogenic p.Arg239Trp variant was documented in the reviewed evidence.	PMID:24130102 PMID:22986143 clinvar
PS2	Not assessed	Not assessed: no documented parental testing proves de novo origin, and all six reported carriers also carried pathogenic c.694C>T in probable cis.	PMID:24130102
PS3	Not assessed	Not assessed: no validated variant-specific functional assay for RAD51D p.Arg239Trp was identified; available reports describe clinical observations or general RAD51D biology.	PMID:22986143 PMID:24130102 PMID:37344587
PS4	Not met	Not met: c.715C>T occurred in two ovarian-cancer patients but also four healthy carriers, without demonstrated variant-specific case-control enrichment.	PMID:24130102 PMID:22986143
PM1	Not met	Not met: p.Arg239Trp is not documented in an approved RAD51D critical domain or statistically significant hotspot.	PMID:37344587
PM2	Not met	Not met: ancestry-specific AF reaches 0.00084317 in gnomAD v4.1, exceeding the generic PM2 threshold of 0.0001 despite low overall AF.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	N/A	Not applicable: RAD51D cancer susceptibility is dominant, and the reported c.715C>T plus pathogenic c.694C>T combination was probably in cis, not biallelic in trans.	PMID:24130102
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002878.4:c.715C>T in RAD51D is a missense substitution predicted to produce NP_002869.3:p.(Arg239Trp). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no established pathogenic alternate missense variant at RAD51D residue Arg239 was documented.	PMID:24130102 PMID:30306255 pm5_candidates
PM6	Not assessed	Not assessed: the six reported carriers lacked documented parental-origin evidence and all also carried pathogenic c.694C>T, probably in cis.	PMID:24130102
PP1	Not assessed	Not assessed: six carriers were reported, but no informative meioses or phase-resolved segregation series isolate c.715C>T from pathogenic c.694C>T.	PMID:24130102
PP2	Not met	Not met: RAD51D disease evidence is predominantly loss-of-function, not an established missense mechanism.	PMID:34923718 PMID:37344587
PP3	Not met	Not met: missense REVEL score 0.287 is below the >=0.644 PP3 supporting threshold.	revel
PP4	Not met	Not met: ovarian cancer is compatible with RAD51D disease but is not sufficiently specific, and c.715C>T was also found in four healthy carriers.	PMID:24130102 PMID:22986143
PP5	Not met	Not met: the exact variant has zero ClinVar expert-panel submissions, so no qualifying Pathogenic or Likely pathogenic classification exists.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum ancestry-specific AF is 0.00084317, far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: the highest observed gnomAD v4.1 ancestry-specific AF is 0.00084317, below the generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD v4.1 reports one homozygote, but age, health status, ascertainment, and phenotype are unavailable for BS2 interpretation.	gnomad_v4 gnomad_v2 PMID:25741868
BS3	Not assessed	Not assessed: no validated variant-specific normal-function assay for RAD51D p.Arg239Trp was identified; clinical observations and computational predictions cannot establish BS3.	PMID:22986143 PMID:24130102 PMID:37344587
BS4	Not assessed	Not assessed: four healthy carriers were reported, but age, pedigree, and phase-resolved data are insufficient to establish non-segregation of c.715C>T.	PMID:24130102
BP1	Met	Met, supporting: RAD51D disease evidence is predominantly loss-of-function while the target is missense.	PMID:34923718 PMID:37344587 pvs1_gene_context
BP2	Not met	Not met: six reported carriers had pathogenic c.694C>T with c.715C>T, and the authors concluded the variants were probably in cis rather than trans.	PMID:24130102 PMID:22986143
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002878.4:c.715C>T in RAD51D is a missense substitution predicted to produce NP_002869.3:p.(Arg239Trp). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting strength: missense REVEL score 0.287 meets the <=0.29 BP4 supporting threshold.	revel
BP5	Met	Met, supporting: c.715C>T repeatedly co-occurred with pathogenic RAD51D c.694C>T, providing an alternate molecular basis for the reported disease.	PMID:24130102 PMID:22986143
BP6	Not met	Not met: two Likely benign ClinVar submissions are non-expert assertions, and the exact variant has zero expert-panel submissions.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002878.4:c.715C>T in RAD51D is a missense substitution predicted to produce NP_002869.3:p.(Arg239Trp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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