NM_002878.4:c.829C>G

RAD51D · NP_002869.3:p.(Leu277Val) · NM_002878.4

GRCh37: chr17:33428294 G>C · GRCh38: chr17:35101275 G>C

Gene: RAD51D Transcript: NM_002878.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RAD51D

Transcript

NM_002878.4

Protein

NP_002869.3:p.(Leu277Val)

gnomAD AF

3.71732471574857e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002878.4:c.829C>G (p.Leu277Val) is a missense variant in RAD51D, a moderate-penetrance hereditary breast and ovarian cancer predisposition gene involved in homologous recombination repair.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.00040% (1/251,446 alleles) and gnomAD v4.1 AF = 0.00037% (6/1,614,064 alleles), meeting PM2 at supporting strength.

Multiple in silico predictors consistently indicate a tolerated or benign effect: REVEL score 0.131, BayesDel score -0.327, and SpliceAI max delta 0.00. These independent computational lines of evidence support BP4 at supporting strength.

No functional studies, case-control data, family segregation analysis, de novo reports, or variant-specific publications were identified for this variant. ClinVar reports Uncertain significance (3 clinical laboratories, 1-star review). OncoKB reports unknown oncogenic effect.

Applying generic ACMG/AMP 2015 combination rules: PM2 (supporting) + BP4 (supporting) yields an overall classification of Uncertain Significance (VUS), consistent with the ClinVar consensus.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, 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	NM_002878.4:c.829C>G is a missense variant (p.Leu277Val). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No pathogenic variant causing the same amino acid change (p.Leu277Val) via a different nucleotide change has been identified in ClinVar or the literature. PS1 requires a previously established pathogenic variant at the same residue with the same amino acid alteration.	clinvar
PS2	Not met	No de novo occurrence data are available for this variant. PS2 requires confirmation that both parents are negative for the variant with parental identity confirmed.
PS3	Not met	No variant-specific functional studies have been reported for NM_002878.4:c.829C>G (p.Leu277Val). OncoKB reports unknown oncogenic effect with no curated functional evidence. The Color Health ClinVar submission explicitly states that functional studies have not been reported for this variant. No publications with experimental functional characterization of this variant or a systematically characterized range encompassing position 277 were identified.	oncokb clinvar
PS4	Not met	No case-control or cohort data demonstrating enrichment of this variant in affected individuals versus controls are available. The variant has been observed in gnomAD at extremely low frequency but no disease-specific prevalence comparison exists.
PS5	Not met	No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance across all three clinical laboratory submissions.	clinvar
PM1	Not met	Position 277 in RAD51D does not lie within a statistically significant mutational hotspot (cancerhotspots.org negative). While RAD51D contains a RecA-like ATPase domain, there is no evidence that position 277 resides in a well-characterized critical functional domain where missense variants are established as pathogenic. Without a VCEP-defined domain map or literature establishing this specific residue as functionally critical, PM1 cannot be applied at the generic ACMG level.
PM2	Met	NM_002878.4:c.829C>G is absent or present at extremely low frequency in population databases. gnomAD v2.1: 1/251,446 alleles (AF = 0.00040%). gnomAD v4.1: 6/1,614,064 alleles (AF = 0.00037%). Both are well below the 0.1% threshold for PM2 application. No homozygotes observed.	gnomad_v2 gnomad_v4
PM5	Not met	PM5 candidate harvesting did not identify any same-residue pathogenic comparator variants at position 277 in RAD51D. No ClinVar entry reports a different missense change at p.Leu277 classified as pathogenic. PM5 requires that a different pathogenic missense variant exists at the same amino acid residue.	pm5_candidates
PM6	Not met	No de novo occurrence of this variant has been reported. PM6 requires confirmation of de novo status with maternity and paternity confirmed.
PP1	Not met	No cosegregation data are available for this variant. PP1 requires observation of the variant cosegregating with disease in multiple affected family members.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. While RAD51D loss-of-function is an established disease mechanism for hereditary breast and ovarian cancer, the HCI prior is not available for this gene, and there is insufficient evidence to establish that missense variants specifically are the predominant disease mechanism. RAD51D-associated cancer risk involves both truncating and missense variants.	pvs1_gene_context
PP3	Not met	Multiple lines of computational evidence suggest this variant is tolerated, not deleterious. REVEL score 0.131 (<0.5 threshold), BayesDel score -0.327 (negative, benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). All available in silico predictors agree on a benign or neutral effect, which contradicts PP3 application.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are provided in the case materials. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar classification for this variant is Uncertain significance (Variation ID 539856), with review status 'criteria provided, single submitter' (1-star). PP5 requires a reputable source to have reported the variant as pathogenic. A 3-star expert panel classification is required for PP5 at supporting strength; this variant has no expert panel review and is classified as VUS by all submitters.	clinvar
BA1	Not met	The variant is extremely rare in population databases. gnomAD v2.1 AF = 0.00040% and v4.1 AF = 0.00037%, both far below the BA1 threshold of >1%. BA1 is not applicable.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency (gnomAD ~0.0004%) is far below the BS1 threshold of >0.3% for a dominant disorder. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available demonstrating observation of this variant in healthy adults at an age when the disease would be expected to have manifested with full penetrance. BS2 requires documented observation in a healthy adult control for a disorder with full penetrance expected at an early age.
BS3	Not met	No well-established functional studies demonstrate that this variant has no damaging effect on protein function or splicing. OncoKB reports unknown oncogenic effect with no curated functional evidence. No publications with experimental characterization of this variant were identified.	oncokb
BS4	Not met	No family segregation data are available to demonstrate lack of cosegregation with disease. BS4 requires observation that the variant does not segregate with disease in affected family members.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. RAD51D-associated hereditary cancer predisposition involves both truncating and missense pathogenic variants. The ACMG clinical practice resource (PMID:41070818) describes RAD51D GPVs broadly without distinguishing variant types as the sole disease mechanism. BP1 is not appropriate for a gene where missense variants are also an established pathogenic mechanism.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in RAD51D has been reported. BP2 requires documented observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4	Met	Multiple independent lines of computational evidence suggest this variant has no deleterious impact on the gene product. REVEL score 0.131 (well below the 0.5 pathogenic threshold, consistent with tolerated prediction). BayesDel score -0.327 (negative, predicting benign effect). SpliceAI max delta 0.00 (no predicted impact on splicing). Three orthogonal in silico approaches converge on a benign or neutral prediction.	revel bayesdel spliceai
BP5	Not met	No data are available showing this variant in a case with an alternative molecular basis for disease. BP5 requires a documented alternate genetic cause explaining the phenotype in a proband who also carries this variant.
BP6	Not met	ClinVar classification for this variant is Uncertain significance, not benign. No reputable source has reported the variant as benign. BP6 requires a 3-star expert panel classification of benign/likely benign; this variant has only 1-star review status and is classified as VUS.	clinvar
BP7	N/A	BP7 applies exclusively to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. NM_002878.4:c.829C>G is a missense variant (p.Leu277Val), not a synonymous variant.

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