Variant classification summary

NM_002878.4:c.270_271dupTA

RAD51D · NP_002869.3:p.(Lys91IlefsTer13) · NM_002878.4

GRCh37: chr17:33434458 T>TTA · GRCh38: chr17:35107439 T>TTA

Gene: RAD51D Transcript: NM_002878.4

Final call

Pathogenic

PVS1 very strong PS3 strong PM2 supporting

Variant details

Gene

RAD51D

Transcript

NM_002878.4

Protein

NP_002869.3:p.(Lys91IlefsTer13)

gnomAD AF

1.679838322022422e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 (very strong) is supported by an early exon 4 frameshift expected to trigger nonsense-mediated decay.

2

Pathogenic: PS3 (strong) is supported by replicated orthogonal assays showing loss of RAD51D homologous-recombination function.

3

Pathogenic: PM2 (supporting) is supported by an aggregate gnomAD allele frequency below 0.0001.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus one strong pathogenic criterion supports a Pathogenic classification.

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	Met	Met, very strong: exon 4 frameshift Lys91IlefsTer13 truncates RAD51D at amino acid 103 of 329 and is expected to trigger NMD.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework PMID:23372765
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_002878.4:c.270_271dup in RAD51D is a frameshift variant predicted to produce NP_002869.3:p.(Lys91IlefsTer13). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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
PS2	Not assessed	Not assessed: no verified parental testing or confirmed de novo occurrence is documented for the proband.
PS3	Met	Met, strong: RAD51D K91fs reduced homologous-recombination repair and RAD51D stability across orthogonal assays with wild-type controls and three biological replicates.	PMID:33151324
PS4	Not assessed	Not assessed: available studies report gene-level enrichment or case prevalence, but no qualifying exact-variant case-control comparison establishes PS4.	PMID:21822267 PMID:23372765 PMID:33151324
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_002878.4:c.270_271dup in RAD51D is a frameshift variant predicted to produce NP_002869.3:p.(Lys91IlefsTer13). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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
PM2	Met	Met at supporting strength: aggregate allele frequency was 1.35305e-05 in gnomAD v3.1 non-cancer genomes, below the 0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no affected-proband observation, second pathogenic RAD51D allele, or confirmed trans phase is documented for this variant.	PMID:23372765 PMID:25741868
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.270_271dup in RAD51D is a frameshift variant predicted to produce NP_002869.3:p.(Lys91IlefsTer13). 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	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_002878.4:c.270_271dup in RAD51D is a frameshift variant predicted to produce NP_002869.3:p.(Lys91IlefsTer13). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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
PM6	Not assessed	Not assessed: no credible apparently de novo case without confirmed parental testing is documented for this variant.
PP1	Not assessed	Not assessed: no affected-family cosegregation data are documented; one cancer-naive control observation is not segregation evidence.	PMID:23372765
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_002878.4:c.270_271dup in RAD51D is a frameshift variant predicted to produce NP_002869.3:p.(Lys91IlefsTer13). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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
PP3	N/A	Not applicable: the variant is a frameshift, outside PP3 scope for missense and splice-region/intronic computational evidence.
PP4	Not assessed	Not assessed: the available case evidence contains no patient phenotype or disease-specific clinical presentation for evaluating PP4.
PP5	Not met	Not met: ClinVar shows laboratory Pathogenic/Likely pathogenic submissions, but zero expert-panel classifications are present for this exact variant.	clinvar
BA1	Not met	Not met: the highest observed allele frequency was 0.00806452, below the 0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: the highest observed allele frequency was 0.00806452, below the 0.01 BS1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not met	Not met: homozygotes were absent from all gnomAD datasets, and the control study reported only one heterozygote among 466 individuals.	gnomad_v2 gnomad_v4 PMID:23372765
BS3	Not met	Not met: RAD51D K91fs showed reduced homologous-recombination repair and protein stability rather than preserved function in assays with wild-type controls.	PMID:33151324
BS4	Not assessed	Not assessed: no informative affected relatives or family non-segregation analysis is documented for this variant.	PMID:23372765
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_002878.4:c.270_271dup in RAD51D is a frameshift variant predicted to produce NP_002869.3:p.(Lys91IlefsTer13). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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
BP2	Not assessed	Not assessed: no cis or trans phase with another pathogenic RAD51D variant is documented in an affected or unaffected individual.	PMID:23372765 PMID:25741868
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.270_271dup in RAD51D is a frameshift variant predicted to produce NP_002869.3:p.(Lys91IlefsTer13). 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	N/A	Not applicable: the variant is a frameshift, outside BP4 scope for missense and splice-region/intronic computational evidence.
BP5	Not assessed	Not assessed: no alternate pathogenic molecular explanation or BP5-specific quantitative evidence is documented for this case.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; available submissions are non-expert laboratory assertions.	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.270_271dup in RAD51D is a frameshift variant predicted to produce NP_002869.3:p.(Lys91IlefsTer13). 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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