Variant classification summary

NM_002878.3:c.26G>C

RAD51D · NP_002869.3:p.(Cys9Ser) · NM_002878.3

GRCh37: chr17:33446607 C>G · GRCh38: chr17:35119588 C>G

Gene: RAD51D Transcript: NM_002878.3

Final call

Likely Benign

PM2 supporting BS2 supporting benign BP1 supporting benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

RAD51D

Transcript

NM_002878.3

Protein

NP_002869.3:p.(Cys9Ser)

gnomAD AF

0.0006561484458336434 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002878.3:c.26G>C (p.Cys9Ser) is a missense variant in exon 1 of RAD51D.

2

This variant is present in gnomAD at a low frequency: 0.0405% (113/278,930 alleles, 1 homozygote) in v2.1 and 0.0656% (1058/1,612,440 alleles, 1 homozygote) in v4.1, with a maximum population frequency of 0.083% in the European (non-Finnish) population (v4.1).

3

The variant has been reported in ClinVar (ID 127886) as Uncertain significance by 10 clinical laboratories and Likely benign by 9 clinical laboratories; no expert panel has reviewed this variant.

4

Multiple lines of computational evidence predict no significant impact on the gene product: REVEL score 0.218, BayesDel score 0.087, and SpliceAI maximum delta score 0.00.

5

PM2 (supporting) is applied because the variant is present at very low frequency in population databases (<0.1% AF in all populations), though weakened by the observation of homozygotes.

6

BP4 (supporting benign) is applied because multiple computational prediction algorithms (REVEL, BayesDel, SpliceAI) support no deleterious effect.

7

BP1 (supporting benign) is applied because RAD51D-associated disease is primarily caused by truncating loss-of-function variants rather than missense changes.

8

BS2 (supporting benign) is applied because one homozygous individual was observed in gnomAD v2.1 and one in gnomAD v4.1, suggesting this variant can be tolerated in at least some individuals.

9

BP6 (supporting benign) is applied because nine independent clinical laboratories have classified this variant as Likely benign with criteria provided.

10

PVS1 is not applicable as this is a missense variant, not a null variant.

11

PS3 is not met because no experimental functional studies have been performed for this variant.

12

PP3 is not met because the aggregate computational evidence supports a benign rather than pathogenic interpretation.

13

Using generic ACMG/AMP 2015 combination rules (PMID:25741868), the evidence profile includes: 1 supporting pathogenic criterion (PM2) and 4 supporting benign criteria (BP1, BP4, BS2, BP6). The net benign evidence outweighs the single pathogenic criterion, supporting a classification of Likely benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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_002878.3:c.26G>C is a missense variant (p.Cys9Ser) located in exon 1; it does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 under the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence was identified that a different nucleotide change at codon 9 resulting in the same amino acid substitution (Cys9Ser) has been previously reported as pathogenic. The variant has been observed in population databases and reported as a variant of uncertain significance or likely benign in ClinVar.	clinvar gnomad_v2 gnomad_v4
PS2	Not assessed	No de novo data are available for this variant. Paternity and maternity were not confirmed.
PS3	Not met	No experimental functional studies have been performed for NM_002878.3:c.26G>C (p.Cys9Ser). OncoKB reports unknown oncogenic effect. One ovarian carcinoma with this variant showed loss of heterozygosity (PMID:22986143), but LOH is an observational tumor finding, not a functional assay demonstrating a deleterious effect. No variant-specific or systematic range functional characterization exists.	oncokb PMID:22986143
PS4	Not met	No case-control study demonstrates statistically significant enrichment of this variant in affected individuals compared to controls. The variant is present in gnomAD at ~0.04–0.07% frequency (113 alleles in v2.1; 1058 alleles in v4.1), which is incompatible with a highly penetrant rare pathogenic variant. One case and zero controls were reported in the Song et al. 2015 case-control study (PMID:26261251), insufficient for statistical significance.	gnomad_v2 gnomad_v4 PMID:26261251
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion.
PM1	Not met	Codon 9 (Cys9) lies in the N-terminal region of RAD51D, outside any established critical functional domain. Cancer Hotspots analysis confirms this position is not a statistically significant mutational hotspot. No literature establishes codon 9 as residing in a well-characterized functional domain whose disruption would satisfy PM1.	oncokb
PM2	Met	This variant is present in gnomAD at very low frequency: v2.1 AF = 0.0405% (113/278,930 alleles) and v4.1 AF = 0.0656% (1058/1,612,440 alleles), with grpmax FAF of 0.065% (v2.1) and 0.079% (v4.1), all below the 0.1% PM2 threshold for non-VCEP assessment. However, the presence of one homozygote in each database and over 100 observed alleles weakens the confidence; thus applied at supporting strength only.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue comparator variants at codon 9 with a different missense change classified as pathogenic were identified in automated PM5 candidate harvesting. Manual review also found no evidence of pathogenic variants at this position in ClinVar or the literature.	pm5_candidates
PM6	Not assessed	No de novo data are available for this variant. No specific de novo report was identified in the literature.
PP1	Not assessed	No co-segregation data are available for this variant.
PP2	Not met	RAD51D-associated disease is primarily driven by loss-of-function (truncating) variants. While rare missense variants can be pathogenic, the gene does not have a well-established low rate of benign missense variation that would satisfy PP2. Multiple common benign missense polymorphisms exist in RAD51D (e.g., p.Arg165Gln, p.Glu233Gly with MAF >1%), indicating a relatively high background of benign missense variation.	gnomad_v2 PMID:24130102
PP3	Not met	Multiple lines of computational evidence predict no damaging effect. REVEL score is 0.218 (well below the 0.5 threshold for pathogenicity). BayesDel score is 0.087 (low). SpliceAI maximum delta score is 0.00, indicating no predicted splicing impact. The aggregate in silico evidence is consistent with a benign interpretation, not supporting PP3.	revel bayesdel spliceai
PP4	Not assessed	No proband phenotype or clinical history was provided for the index case. Variant-level phenotype specificity cannot be evaluated without patient-level data.
PP5	Not met	No reputable source has classified this variant as pathogenic. ClinVar reports this variant as Uncertain significance (10 clinical laboratories) and Likely benign (9 clinical laboratories) under variation ID 127886. No expert panel has asserted pathogenicity.	clinvar
BA1	Not met	The maximum observed allele frequency in gnomAD is 0.083% (v4.1 NFE), well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum observed allele frequency in gnomAD is 0.083% (v4.1 NFE), below the 0.3% BS1 threshold for non-VCEP assessment.	gnomad_v2 gnomad_v4
BS2	Met	One homozygous individual is observed in gnomAD v2.1 and one homozygous individual is observed in gnomAD v4.1. RAD51D-associated cancer predisposition is adult-onset with moderate penetrance, so homozygous observation does not definitively exclude pathogenicity, but it provides supporting evidence that the variant can be tolerated in at least some individuals. Applied at supporting benign strength.	gnomad_v2 gnomad_v4
BS3	Not met	No in vitro or in vivo functional studies have been performed to evaluate the effect of p.Cys9Ser on RAD51D protein function. The absence of functional data does not satisfy BS3, which requires positive evidence of no damaging effect from well-established functional assays.	oncokb
BS4	Not assessed	No co-segregation data are available to evaluate lack of segregation with disease in affected families.
BP1	Met	RAD51D is a gene in which the primary disease mechanism is loss-of-function through truncating variants (nonsense, frameshift, canonical splice). The ACMG/AMP 2015 guidelines (PMID:25741868) specify BP1 for missense variants in genes where primarily truncating variants cause disease. The RAD51D locus is well-characterized as an ovarian cancer susceptibility gene where the vast majority of reported pathogenic variants are protein-truncating.	PMID:25741868 PMID:21822267 PMID:26261251
BP2	Not assessed	No data are available regarding observation of this variant in trans with a known pathogenic variant in RAD51D.
BP4	Met	Multiple lines of computational evidence support a benign interpretation. REVEL score is 0.218 (benign-leaning, well below the 0.5 threshold). BayesDel score is 0.087 (low, consistent with benign). SpliceAI delta score is 0.00 (no predicted splicing impact). SIFT predicts tolerated (PMID:24130102). The aggregate in silico evidence indicates no significant impact on gene product.	revel bayesdel spliceai PMID:24130102
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in a proband carrying this variant.
BP6	Met	Nine clinical laboratories in ClinVar have classified this variant as Likely benign (variation ID 127886). Multiple reputable clinical testing laboratories independently arrived at a likely benign classification with criteria provided, including Ambry Genetics, LabCorp, and Quest Diagnostics. This represents a substantial body of clinical laboratory consensus favoring a benign interpretation.	clinvar
BP7	N/A	NM_002878.3:c.26G>C is a missense variant (p.Cys9Ser), not a synonymous or intronic variant. BP7 applies to synonymous variants for which splicing prediction algorithms predict no impact, not to missense substitutions.
BP3	N/A	BP3 was specified as trivially not applicable (in-frame deletion/insertion in non-repetitive region). This is a substitution variant.
PM3	N/A	PM3 was specified as trivially not applicable. RAD51D-associated disease displays autosomal dominant inheritance; there is no evidence for a recessive mode of inheritance. No data on trans observations are available.
PM4	N/A	PM4 was specified as trivially not applicable. This is a substitution variant, not a protein length-altering variant (in-frame deletion/insertion or stop-loss).

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