Variant classification summary

NM_002878.3:c.641C>T

RAD51D · NP_002869.3:p.(Pro214Leu) · NM_002878.3

GRCh37: chr17:33430499 G>A · GRCh38: chr17:35103480 G>A

Gene: RAD51D Transcript: NM_002878.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

RAD51D

Transcript

NM_002878.3

Protein

NP_002869.3:p.(Pro214Leu)

gnomAD AF

1.2390928848808365e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=0.000124%, 2/1,614,084 alleles, 0 homozygotes), meeting PM2 at supporting strength.

2

Multiple in silico tools predict no damaging effect: REVEL score 0.266, BayesDel score 0.181, and SpliceAI max delta 0.00, meeting BP4 at supporting benign strength.

3

The variant has been reported in ClinVar as Uncertain significance by five clinical laboratories (Variation ID: 574602). No expert panel review or pathogenic/benign classification has been rendered.

4

No variant-specific functional studies, cosegregation data, de novo observations, or case-control enrichment data are available. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence.

5

The opposing PM2 (supporting) and BP4 (supporting benign) criteria effectively cancel each other, yielding an evidence framework consistent with 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
PVS1	N/A	This is a missense variant (c.641C>T, p.Pro214Leu), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The ClinGen SVI PVS1 decision tree does not apply to missense substitutions.	pvs1_variant_assessment
PS1	Not assessed	No data available to determine whether a different nucleotide change at the same amino acid residue (Pro214) has been established as pathogenic.
PS2	Not assessed	No de novo observation with confirmed maternity and paternity is available for this variant.
PS3	Not met	No variant-specific functional studies were identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence for this variant. No publication with functional experimental data for NM_002878.3:c.641C>T was found.	oncokb
PS4	Not assessed	No case-control or cohort data comparing variant prevalence in affected individuals versus controls is available. The ClinVar submissions do not include case counts or odds ratios.
PS5	Not met	No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance from all 5 clinical laboratories; no expert panel review has been performed.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot per CancerHotspots.org, and no domain-level constraint or functional domain data specific to RAD51D missense constraint is available to support PM1 application.
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at an extremely low allele frequency in gnomAD v4.1 (AF=0.000124%, 2/1,614,084 alleles, 0 homozygotes). Well below the 0.1% PM2 threshold for dominant disorders.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No established pathogenic missense variant at the same residue (Pro214) with a different amino acid change is available. PM5 candidate harvesting returned no comparators.	pm5_candidates
PM6	Not assessed	No de novo observation (maternity/paternity unconfirmed) has been reported for this variant.
PP1	Not assessed	No cosegregation data with disease in families is available for this variant.
PP2	Not assessed	No HCI prior or other gene-level constraint metric is available for RAD51D (gene_not_supported in HCI prior lookup). Cannot assess whether RAD51D has a low rate of benign missense variation.
PP3	Not met	Multiple in silico tools do not support a deleterious effect. REVEL score is 0.266 (below the 0.5 damaging threshold). BayesDel score is 0.181 (below common 0.2–0.3 damaging thresholds). SpliceAI max delta is 0.00 (no splice impact).	revel bayesdel spliceai
PP4	Not assessed	No detailed clinical phenotype or family history data are available for the probands carrying this variant. ClinVar submissions lack specific phenotype descriptions.
PP5	Not met	No reputable source has reported this variant as pathogenic. All five ClinVar submitters classify it as Uncertain significance. No expert panel classification exists.	clinvar
BA1	Not met	The maximum allele frequency (gnomAD v4.1 NFE: 0.00017%) is well below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The maximum allele frequency (gnomAD v4.1 NFE: 0.00017%) is well below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	No data on observation in healthy adult controls for a fully penetrant early-onset disorder. The 2 gnomAD alleles lack phenotype data to confirm healthy status or exclude late-onset disease.
BS3	Not met	No well-established functional studies demonstrating no damaging effect on protein function or splicing are available. OncoKB reports no variant-specific functional evidence.	oncokb
BS4	Not assessed	No segregation data demonstrating absence of cosegregation with disease is available.
BP1	Not assessed	RAD51D loss of function is an established disease mechanism, but missense variants can also be pathogenic via dominant-negative or hypomorphic effects. Without gene-specific data on the proportion of pathogenic variants that are truncating versus missense, BP1 cannot be reliably applied.
BP2	Not assessed	No data on observation in trans with a known pathogenic variant in RAD51D.
BP3	N/A	This variant is a missense substitution, not an in-frame indel in a non-repeat region.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.266 (below the 0.5 damaging threshold), BayesDel score is 0.181 (below common 0.2–0.3 damaging thresholds), and SpliceAI max delta is 0.00 (no predicted splice impact).	revel bayesdel spliceai
BP5	Not assessed	No data on observation of this variant in cases with an alternative molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign. ClinVar classification is Uncertain significance; no benign classification exists from any clinical laboratory.	clinvar
BP7	N/A	This is a missense variant (c.641C>T, p.Pro214Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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