Variant classification summary

NM_058216.3:c.571+15G>T

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

GRCh37: chr17:56774235 G>T · GRCh38: chr17:58696874 G>T

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

1.611725426456349e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (supporting, pathogenic direction): gnomAD v4.1 allele frequency 0.0000161 (26/1,613,178; grpmax FAF 0.0000138) sits below the 0.0001 rarity threshold.

2

BP4 (supporting, benign direction): SpliceAI max delta 0.006 predicts no impact on splicing in this intronic variant.

3

Not applied: PVS1 not applicable (non-canonical intronic change, no null-variant class, no splice effect), BA1/BS1/BS2 not met (frequency far below thresholds), PP5/BP6 not met (no expert-panel assertion), PM1/PM3/PM4/PM5/PP2/BP1/BP2/BP3/BP7 not met or not applicable.

Final determination: Under the generic ACMG/AMP 2015 combination rules no pathogenic combination is reached (no PVS1, PS or >=2 PM criteria; only one supporting-level PM2) and no benign or likely-benign combination is reached (no BA1, no BS criterion, and a single supporting BP4 does not satisfy the 2-BP rule), so the one pathogenic-direction and one benign-direction supporting criteria conflict and the variant is classified 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	Not applicable: c.571+15G>T is a deep intronic non-canonical variant (SpliceAI max delta 0.006), not a null variant, and no RNA evidence exists.	cspec spliceai pvs1_generic_framework PMID:25741868
PS1	N/A	Not applicable: c.571+15G>T is intronic with predicted consequence p.?, so it produces no amino-acid change to match against an established pathogenic variant.	cspec PMID:25741868 PMID:25394175
PS2	Not assessed	Not assessed: no proband and no parental/trio testing data exist in this case, so a confirmed de novo occurrence cannot be evaluated.	cspec PMID:25741868 clinvar
PS3	Not assessed	Not assessed: no RNA or protein functional assay has been reported for RAD51C c.571+15G>T, so PS3 has no assay evidence.	PMID:25741868 cspec clinvar
PS4	Not assessed	Not assessed: no case-control data or affected probands exist for c.571+15G>T, so no enrichment statistic could be compared.	clinvar cspec PMID:20301575 PMID:25394175 PMID:25741868 PMID:28492532
PM1	Not met	Not met: c.571+15G>T is intronic (intron 3, p.?) with no residue inside any RAD51C critical domain or hotspot, and no VCEP domain table exists for this gene.	cspec final_classification_framework spliceai clinvar PMID:25741868
PM2	Met	Met (supporting): gnomAD v4.1 total allele frequency 0.0000161 (26/1,613,178; grpmax FAF 0.0000138) is below the 0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 cspec PMID:25741868
PM3	Not met	Not met: no trans-with-pathogenic RAD51C observation exists; all four ClinVar submitters report likely benign without any phasing evidence for this intronic variant.	cspec clinvar PMID:25741868
PM4	N/A	Not applicable: c.571+15G>T is intronic with no protein-length change (p.?), so the PM4 in-frame indel/stop-loss requirement is not met.	cspec spliceai PMID:25741868
PM5	N/A	Not applicable: c.571+15G>T alters no codon (p.?), so there is no residue at which a different pathogenic missense could be compared.	pm5_candidates cspec PMID:25741868
PM6	Not assessed	Not assessed: no proband and no parental genotypes of any kind were reported, so no assumed de novo event could be evaluated.	cspec PMID:25741868 clinvar
PP1	Not assessed	Not assessed: zero family members or informative meioses are documented, so co-segregation with disease cannot be observed.	cspec PMID:25741868 clinvar
PP2	N/A	Not applicable: PP2 is restricted to missense variants, and c.571+15G>T is intronic with no amino-acid substitution (p.?).	cspec PMID:25741868
PP3	Not met	Not met: SpliceAI max delta 0.006 falls far below the >=0.2 supporting PP3 threshold.	spliceai cspec
PP4	Not assessed	Not assessed: no proband phenotype or family history is available to test specificity for RAD51C.	clinvar cspec PMID:25741868
PP5	Not met	Not met: the exact-variant ClinVar record has four non-expert laboratory submissions and zero expert-panel assertions.	clinvar cspec PMID:25741868
BA1	Not met	Not met: the highest observed allele frequency, 0.00018 in a small 'Remaining individuals' bin, is far below the 0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 cspec PMID:25741868
BS1	Not met	Not met: dataset allele frequencies of 0.0000161 (gnomAD v4.1) and 0.0000203 (v3.1 non-cancer genomes) are far below the 0.01 BS1 threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	Not met: only one homozygous adult is reported (gnomAD v4.1, 26/1,613,178 alleles) and RAD51C cancer risk is adult-onset with reduced penetrance, failing BS2's healthy-adult requirement.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no functional assay shows normal splicing or preserved RAD51C function for c.571+15G>T, so BS3 lacks its required supporting evidence.	PMID:25741868 cspec clinvar
BS4	Not assessed	Not assessed: no pedigree or relative genotypes exist, so non-segregation in a family cannot be demonstrated by any source.	cspec PMID:25741868 clinvar
BP1	N/A	Not applicable: BP1 is limited to missense variants, and c.571+15G>T is intronic with no amino-acid substitution (p.?).	pvs1_gene_context cspec PMID:25741868
BP2	Not met	Not met: no cis/trans phase relationship with a pathogenic RAD51C variant exists; gnomAD v4.1's lone homozygote (26/1,613,178 alleles) is not trans-with-pathogenic evidence.	cspec clinvar gnomad_v2 gnomad_v4 PMID:25741868
BP3	N/A	Not applicable: c.571+15G>T is a single-nucleotide intronic substitution (p.?), not an in-frame indel in a repeat region as BP3 requires.	cspec PMID:25741868
BP4	Met	Met (supporting): SpliceAI max delta 0.006 is below the <=0.1 BP4 supporting threshold.	spliceai cspec
BP5	Not assessed	Not assessed: no proband or case-level data exist to show an alternate molecular basis for disease.	clinvar cspec PMID:25741868
BP6	Not met	Not met: ClinVar reports Likely benign from four non-expert laboratories, with no expert-panel assertion to trigger BP6.	clinvar cspec PMID:25741868
BP7	N/A	Not applicable: c.571+15G>T is intronic, not a synonymous variant, so BP7's scope is not met.

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