Variant classification summary

NM_058216.3:c.905-19T>C

RAD51C · NP_478123.1:p.? · NM_058216.3

GRCh37: chr17:56801382 T>C · GRCh38: chr17:58724021 T>C

Gene: RAD51C Transcript: NM_058216.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RAD51C

Transcript

NM_058216.3

Protein

NP_478123.1:p.?

gnomAD AF

5.628926176007765e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD allele frequency 0.0088% (v2.1) and 0.0057% (v4.1), both below the 0.1% rarity threshold.

2

BP4 (Supporting): SpliceAI max delta 0.016, below the 0.1 threshold, indicating no predicted splicing impact.

3

Variant of Uncertain Significance: PM2 (supporting pathogenic) and BP4 (supporting benign) oppose each other, satisfying no Benign, Likely Benign, Likely Pathogenic, or Pathogenic combination rule under ACMG/AMP 2015.

Final determination: Generic ACMG/AMP 2015 combination rules require thresholds not met by a single supporting pathogenic criterion (PM2) combined with a single supporting benign criterion (BP4); this conflicting/insufficient combination defaults to 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	Not applicable: a deep intronic change 19 bp upstream of the splice acceptor is not a canonical splice-site or other null variant.	pvs1_gene_context pvs1_variant_assessment spliceai pvs1_generic_framework
PS1	N/A	Not applicable: PS1 requires the same amino acid change as an established pathogenic variant, undefined for a non-coding intronic substitution.
PS2	Not assessed	Not assessed: no de novo observation or parental-testing data were available for this variant.	cspec PMID:25741868
PS3	Not assessed	Not assessed: no validated functional assay data (splicing minigene, RT-PCR, or HDR assay) were available.
PS4	Not assessed	Not assessed: no case-control or statistical enrichment evidence for this variant was available.	cspec clinvar
PM1	N/A	Not applicable: PM1 requires a missense change in a mutational hotspot; this variant is intronic.
PM2	Met	Met (supporting): gnomAD allele frequency 0.0088% (v2.1) and 0.0057% (v4.1), both below the 0.1% PM2 rarity threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no biallelic observation or second pathogenic/likely pathogenic RAD51C variant was reported.	cspec
PM4	N/A	Not applicable: PM4 requires an in-frame indel or stop-loss change; this is an intronic substitution.	spliceai
PM5	N/A	Not applicable: PM5 requires a missense change at a residue with an established pathogenic variant; no residue is altered here.
PM6	Not assessed	Not assessed: no reported de novo occurrence or parental testing was available.	cspec PMID:25741868
PP1	Not assessed	Not assessed: no segregation data from informative relatives were reported.	cspec PMID:25741868
PP2	N/A	Not applicable: PP2 applies only to missense variants; this variant produces no missense change.
PP3	Not met	Not met: SpliceAI max delta 0.016, well below the >0.2 PP3 splice-path threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no phenotype or personal/family cancer history was provided for the tested individual.	cspec
PP5	Not met	Not met: no ClinVar expert-panel pathogenic or likely pathogenic classification exists for this exact variant.	clinvar
BA1	Not met	Not met: highest gnomAD allele frequency 0.0088%, far below the >1% BA1 stand-alone benign threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest observed gnomAD allele frequency 0.038% (NFE_SWE subset), below the >0.3% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD reports zero homozygotes and no disease-free carrier phenotype is established.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated functional assay with normal-range results was available.
BS4	Not assessed	Not assessed: no affected non-carrier or unaffected carrier observations were reported.	cspec PMID:25741868
BP1	N/A	Not applicable: BP1 applies only to missense variants in genes where truncation is the primary mechanism.
BP2	Not assessed	Not assessed: no co-occurrence data with a pathogenic RAD51C variant, or cis/trans phase, were reported.	cspec
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repetitive region; this is an intronic substitution.
BP4	Met	Met (supporting): SpliceAI max delta 0.016, below the <0.1 BP4 threshold, indicating no predicted splice impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no evidence of an alternative molecular diagnosis was available.
BP6	Not met	Not met: no ClinVar expert-panel benign or likely benign classification exists for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous coding variants; this is a deep intronic change.

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