Variant classification summary

NM_002878.4:c.198G>T

RAD51D · NP_002869.3:p.(Val66=) · NM_002878.4

GRCh37: chr17:33445585 C>A · GRCh38: chr17:35118566 C>A

Gene: RAD51D Transcript: NM_002878.4

Final call

Likely Benign

BS1 supporting BP6 supporting BP7 supporting

Variant details

Gene

RAD51D

Transcript

NM_002878.4

Protein

NP_002869.3:p.(Val66=)

gnomAD AF

9.726168100398835e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002878.4:c.198G>T (p.Val66=) is a synonymous variant in RAD51D with no predicted amino acid change.

2

SpliceAI predicts no splice impact for this variant (max delta score = 0.00), meeting BP7 (supporting).

3

This variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.303% and an East Asian subpopulation frequency of 0.348% (156/44,880 alleles, one homozygote), marginally exceeding the 0.3% threshold for BS1 at supporting strength.

4

Multiple clinical diagnostic laboratories have classified this variant as Likely benign (5 labs) or Benign (1 lab) in ClinVar (Variation ID: 184496), consistent with BP6 at supporting strength.

5

No variant-specific functional, segregation, de novo, or case-control data were identified in the literature. Three PMIDs from ClinVar (25741868, 25394175, 28492532) are guideline or methods papers that do not mention NM_002878.4:c.198G>T.

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_002878.4:c.198G>T is a synonymous variant (p.Val66=) that does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is not applicable to synonymous variants.	pvs1_generic_framework
PS1	N/A	PS1 requires a same amino acid change as a previously established pathogenic variant. This is a synonymous variant (p.Val66=) with no amino acid change; the PS1 concept does not apply to synonymous variants.
PS2	Not assessed	No de novo data available for NM_002878.4:c.198G>T.
PS3	Not assessed	No well-established functional studies identified for this specific variant. The three PMIDs from ClinVar are guideline/methods papers (25741868, 25394175, 28492532) that do not contain variant-specific functional data.
PS4	Not met	The variant is present in gnomAD at low frequency (v2.1: 0.004%, v4.1: 0.010%) with one homozygote in v4.1. No case-control data show enrichment in affected individuals; prevalence in the general population does not support pathogenicity.	gnomad_v2 gnomad_v4
PS5	Not assessed	No reputable source has reported NM_002878.4:c.198G>T as pathogenic. ClinVar classification is Likely benign/Benign.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot in RAD51D.
PM2	Not assessed	While the overall gnomAD allele frequency is below the 0.1% PM2 threshold (v2.1: 0.004%, v4.1: 0.010%), the gnomAD v4.1 grpmax filtering allele frequency is 0.303%, meeting BS1. BS1 provides stronger population-level evidence in the benign direction and supersedes PM2. PM2 is therefore not assessed independently.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a novel missense amino acid change at the same residue as a known pathogenic missense variant. NM_002878.4:c.198G>T is synonymous (p.Val66=) and has no amino acid change; PM5 does not apply. Confirmed by pm5_candidates.json: residue context could not be parsed for a synonymous variant.
PM6	Not assessed	No de novo data available for NM_002878.4:c.198G>T.
PP1	Not assessed	No segregation data available for NM_002878.4:c.198G>T.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. NM_002878.4:c.198G>T is a synonymous variant (p.Val66=); PP2 does not apply to synonymous variants.
PP3	N/A	PP3 applies when multiple lines of computational evidence support a deleterious effect. This is a synonymous variant (p.Val66=) with SpliceAI max delta score of 0.00 (no predicted splice impact). REVEL and BayesDel scores are unavailable for synonymous variants. Computational evidence does not support pathogenicity; BP7 is the applicable criterion.	spliceai
PP4	Not assessed	No phenotype or disease-specificity data available for NM_002878.4:c.198G>T.
PP5	Not met	PP5 requires a reputable source to report the variant as pathogenic. ClinVar classification for this variant is Likely benign (7 clinical laboratories) and Benign (1 clinical laboratory). No reputable source has reported it as pathogenic.	clinvar
BA1	Not met	The gnomAD grpmax filtering allele frequency is 0.303% (v4.1), which is well below the 1% BA1 threshold. BA1 requires allele frequency >1% in a population database.	gnomad_v4
BS1	Met	The gnomAD v4.1 grpmax filtering allele frequency is 0.303%, marginally exceeding the 0.3% threshold for BS1. In the East Asian subpopulation, the allele frequency is 0.348% (156/44,880 alleles) with one homozygote observed, indicating the variant is too common in the general population to be a highly penetrant pathogenic variant for RAD51D-associated autosomal dominant cancer predisposition. The borderline frequency and the v2.1 grpmax FAF of 0.022% (below threshold) warrant supporting rather than strong strength.	gnomad_v4 gnomad_v2
BS2	Not assessed	While one homozygote is observed in gnomAD v4.1, the individuals in gnomAD are not specifically confirmed as healthy adults. RAD51D has moderate/incomplete penetrance with adult-onset cancer, limiting the applicability of BS2 which requires full penetrance expected at an early age.	gnomad_v4
BS3	Not assessed	No well-established functional studies showing no damaging effect were identified for NM_002878.4:c.198G>T. The synonymous nature and SpliceAI delta of 0.00 are computational, not functional, evidence.
BS4	Not assessed	No segregation data available for NM_002878.4:c.198G>T.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary pathogenic mechanism. NM_002878.4:c.198G>T is a synonymous variant (p.Val66=); BP1 does not apply.
BP2	Not assessed	No data on observation of NM_002878.4:c.198G>T in trans with a known pathogenic RAD51D variant.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions. NM_002878.4:c.198G>T is a single nucleotide substitution, not an in-frame indel.
BP4	Not assessed	BP4 (multiple lines of computational evidence suggest no impact) is subsumed by BP7 for this synonymous variant. SpliceAI delta = 0.00 supports the absence of splice impact. BP7 provides the more specific assessment.	spliceai
BP5	N/A	BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No alternate molecular basis has been identified, and BP5 is not independently assessed in the absence of such evidence.
BP6	Met	Multiple reputable clinical diagnostic laboratories have classified NM_002878.4:c.198G>T as Likely benign (Labcorp/Invitae, Color Health, GeneDx, Ambry Genetics, Counsyl) or Benign (Myriad Genetics) in ClinVar (Variation ID: 184496). The underlying evidence criteria are not publicly available for independent evaluation, so BP6 is applied at supporting strength.	clinvar
BP7	Met	NM_002878.4:c.198G>T is a synonymous variant (p.Val66=) with no predicted amino acid change. SpliceAI predicts no splice impact (max delta score = 0.00), and no novel splice site creation is predicted. This meets the ACMG/AMP BP7 criterion for synonymous variants without predicted splicing consequences.	spliceai
PM3	N/A	PM3 applies to recessive disorders when the variant is detected in trans with a pathogenic variant. RAD51D is associated with autosomal dominant cancer predisposition; PM3 does not apply.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. NM_002878.4:c.198G>T is a synonymous substitution with no protein length change.

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