NM_002878.3:c.422T>C

RAD51D · NP_002869.3:p.(Leu141Pro) · NM_002878.3

GRCh37: chr17:33434065 A>G · GRCh38: chr17:35107046 A>G

Gene: RAD51D Transcript: NM_002878.3

Final call

VUS

PM2 supporting

Variant details

Gene

RAD51D

Transcript

NM_002878.3

Protein

NP_002869.3:p.(Leu141Pro)

gnomAD AF

1.1151531972681225e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002878.3:c.422T>C (p.Leu141Pro) is a missense variant in RAD51D, a moderate-penetrance ovarian cancer predisposition gene where loss-of-function is the established disease mechanism.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.0004% (1/251,470 alleles) and gnomAD v4.1 AF=0.0011% (18/1,614,128 alleles), and is absent from gnomAD-Canada. PM2 (supporting) is met.

ClinVar reports this variant as Uncertain significance by seven clinical laboratories with review status 'criteria provided, single submitter.' No expert panel pathogenic or benign classification exists.

In silico predictions are mixed: REVEL score 0.44 (indeterminate), BayesDel score 0.07 (benign), and SpliceAI max delta 0.04 (no splice impact). These do not meet PP3 or BP4 thresholds.

No functional studies, case-control data, cosegregation data, or de novo observations are available for this variant. PS3, PS4, PP1, PS2, and PM6 remain unassessed.

No same-residue pathogenic comparator exists at Leu141, precluding PS1 and PM5 application.

RAD51D has both established pathogenic truncating and missense variants; BP1 is not met because missense variants cannot be presumed benign in this gene.

Overall, this variant meets only PM2 (supporting). All other applicable criteria are either not met or cannot be assessed due to insufficient evidence. The variant remains of uncertain significance.

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
BP3	N/A	NM_002878.3:c.422T>C is a single-nucleotide substitution, not an in-frame insertion/deletion or stop-loss variant. BP3 applies only to in-frame indels in repetitive regions without a known function.
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. RAD51D-associated cancer predisposition is not a recessive disorder in this context.
PM4	N/A	NM_002878.3:c.422T>C is a single-nucleotide substitution, not an in-frame deletion/insertion or stop-loss variant. PM4 applies only to non-repeat region protein length changes.
PVS1	N/A	NM_002878.3:c.422T>C is a missense substitution (p.Leu141Pro). This variant does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 application per the ClinGen SVI PVS1 framework (PMC6185798). PVS1 is not applicable to missense variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No known pathogenic variant with a different amino acid change at the same residue (Leu141) was identified. PM5 candidate search found zero same-residue comparator variants in ClinVar. PS1 cannot be applied without evidence of a different pathogenic missense change at this position.	pm5_candidates
PS2	Not assessed	No de novo data available for NM_002878.3:c.422T>C. None of the reviewed publications or ClinVar submissions report de novo occurrence of this variant.
PS3	Not assessed	No variant-specific functional studies identified. OncoKB reports unknown oncogenic effect for this variant. Literature review found no functional characterization of NM_002878.3:c.422T>C (p.Leu141Pro) in any experimental system.	oncokb
PS4	Not assessed	No case-control or cohort studies comparing the prevalence of NM_002878.3:c.422T>C in affected vs. unaffected individuals were identified. The variant has been observed in clinical testing and reported as VUS by seven laboratories, but no statistically enriched case series or odds-ratio data are available.	clinvar
PS5	N/A	PS5 applies to variants found in trans with a pathogenic variant for recessive disorders. RAD51D-associated cancer predisposition is not a recessive disorder in this context, and no trans configuration data exist for this variant.
PM1	Not met	Leu141 does not lie in a statistically significant mutational hotspot in RAD51D. No evidence supports that this residue falls within a well-established functional domain without benign variation.
PM2	Met	NM_002878.3:c.422T>C is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-06 (1/251,470 alleles, 0.0004%) and gnomAD v4.1 AF=1.12e-05 (18/1,614,128 alleles, 0.0011%). Both are well below the 0.1% threshold for PM2. Absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants at Leu141 were identified in ClinVar. PM5 requires a different pathogenic missense change at the same amino acid position; automated candidate harvesting found zero eligible comparators.	pm5_candidates
PM6	Not assessed	No de novo data available. PM6 requires confirmation of de novo occurrence with confirmed maternity and paternity; no such evidence was identified for this variant in any reviewed source.
PP1	Not assessed	No cosegregation data available. PP1 requires demonstration of variant cosegregation with disease in multiple affected family members; no family studies were identified for this variant.
PP2	Not met	PP2 requires a gene where missense variants are a common mechanism of disease AND the gene has a low rate of benign missense variation. In RAD51D, the primary disease mechanism is loss-of-function through truncating variants; missense variants can be pathogenic but are not the predominant mechanism. This criterion is not met.
PP3	Not met	In silico predictions are mixed and do not consistently support a deleterious effect. REVEL score is 0.44 (indeterminate, below the 0.5 pathogenic threshold). BayesDel score is 0.07 (benign range). SpliceAI max delta is 0.04 (no predicted splice impact). Multiple lines of computational evidence do NOT converge on a deleterious prediction.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for RAD51D-associated disease.
PP5	Not met	No reputable source has recently reported NM_002878.3:c.422T>C as pathogenic. ClinVar reports this variant as Uncertain significance from seven clinical laboratories, with review status 'criteria provided, single submitter.' No expert panel classification is available.	clinvar
BA1	Not met	gnomAD v4.1 allele frequency is 0.0011% (1.12e-05), well below the 1% threshold for BA1. The variant is not common in any population.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD v4.1 allele frequency is 0.0011%, well below the 0.3% threshold for BS1. The variant is not observed at a frequency greater than expected for the disorder.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on observation of this variant in healthy adults where full penetrance would be expected at an early age. BS2 requires observation in controls where disease would have manifested if the variant were pathogenic.
BS3	Not assessed	No functional studies have been performed on NM_002878.3:c.422T>C (p.Leu141Pro) that demonstrate no damaging effect on protein function or splicing.
BS4	Not assessed	No cosegregation data demonstrating lack of segregation with disease are available for this variant.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease. While RAD51D loss-of-function is an established disease mechanism, pathogenic missense variants in RAD51D are also well-documented (e.g., in the ACMG clinical practice resource PMID:41070818). Missense variants at this gene cannot be presumed benign solely because truncating variants are pathogenic.	pvs1_gene_context
BP2	Not assessed	No data on observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No phasing data are available.
BP4	Not met	Computational evidence does not consistently suggest no impact. BayesDel score of 0.07 supports a benign interpretation, but REVEL score of 0.44 falls in the indeterminate range (neither clearly benign nor pathogenic). SpliceAI shows no splicing effect (max delta 0.04). The mixed signal does not satisfy the requirement for multiple lines of computational evidence converging on no impact.	revel bayesdel spliceai
BP5	N/A	BP5 applies when a variant is observed in a case with an alternate molecular basis for disease. No such observation exists for this variant; the criterion is not applicable in the absence of an alternate molecular diagnosis.
BP6	Not met	No reputable source has recently reported NM_002878.3:c.422T>C as benign. ClinVar classification is Uncertain significance. BP6 requires a reputable source reporting the variant as benign without access to primary data for independent evaluation.	clinvar
BP7	N/A	NM_002878.3:c.422T>C is a missense variant (p.Leu141Pro), not a synonymous/silent variant. BP7 specifically applies to synonymous variants with no predicted splice impact.

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