Variant classification summary

NM_058216.3:c.904+5G>T

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

GRCh37: chr17:56798178 G>T · GRCh38: chr17:58720817 G>T

Gene: RAD51C Transcript: NM_058216.3

Final call

Pathogenic

PVS1 very strong PS3 strong PM2 supporting PP3 supporting

Variant details

Gene

RAD51C

Transcript

NM_058216.3

Protein

NP_478123.1:p.?

gnomAD AF

8.734528965569735e-06 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): exon 6 exclusion produces the frameshift V280GfsX11, predicted to trigger nonsense-mediated decay.

2

PS3 (Strong): patient tumor RNA from two carriers and an independent minigene assay both reproduced variant-caused exon 6 skipping.

3

PM2 (Supporting): absent or ultra-rare in population databases, with gnomAD v4.1 frequency 0.000873% and no homozygotes.

4

PP3 (Supporting): SpliceAI maximum delta 0.949 predicts a splice impact, above the >0.2 threshold.

5

Overall classification: Pathogenic, from PVS1 (Very Strong) plus PS3 (Strong) under the generic ACMG/AMP combination rule.

Final determination: Under the generic ACMG/AMP 2015 fallback rules, one very strong pathogenic criterion plus one strong pathogenic criterion results in a Pathogenic classification.

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	Met	Met (Very Strong): c.904+5G>T causes exon 6 exclusion, producing the frameshift V280GfsX11 predicted to trigger nonsense-mediated decay.	cspec pvs1_generic_framework pvs1_gene_context PMID:20400964
PS1	N/A	Not applicable: this is an intron 6 splice-region variant with protein consequence p.?, so no same-amino-acid missense change exists to compare.	cspec PMID:20400964 PMID:34299313
PS2	Not assessed	Not assessed: the exact variant appears in hereditary breast and ovarian cancer pedigrees, but no parental genotypes or confirmed de novo occurrence are documented.	cspec PMID:20400964 PMID:34299313
PS3	Met	Met (Strong): patient tumor RNA from two carriers and an independent minigene reporter both reproduced variant-caused exon 6 exclusion.	cspec PMID:20400964
PS4	Not assessed	Not assessed: the variant appears in affected breast and ovarian cancer cohorts, but no case-control enrichment statistic or specified counts were available.	PMID:20400964 PMID:34299313
PM1	N/A	Not applicable: the variant has no defined protein residue or missense consequence to score against a critical domain or mutational hotspot.	cspec PMID:20400964 PMID:34299313
PM2	Met	Met (Supporting): ultra-rare in population databases at gnomAD v4.1 frequency 0.000873% (14/1,602,834 alleles), with no homozygotes observed.	cspec generic_acmg_combination_rules gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: reported in breast and ovarian cancer pedigrees, but no confirmed biallelic, in-trans, or compound-heterozygous Fanconi anemia case establishes PM3.	cspec PMID:20400964 PMID:34299313
PM4	N/A	Not applicable: exon 6 skipping causes a frameshift with premature termination (V280GfsX11), not an in-frame protein length change.	PMID:20400964
PM5	N/A	Not applicable: PM5 requires a pathogenic missense change at the same amino-acid residue, but this variant is intronic with protein consequence p.?.	cspec PMID:20400964 PMID:34299313
PM6	Not assessed	Not assessed: reports describe inherited cancer pedigrees without parental genotypes or a confirmed de novo occurrence for this variant.	cspec PMID:20400964 PMID:34299313
PP1	Not assessed	Not assessed: two cancer pedigrees are reported, but no countable meioses, relative genotypes, or segregation statistic were available.	cspec PMID:20400964 PMID:34299313
PP2	N/A	Not applicable: this is not a missense variant, so the gene's pathogenic-missense proportion is not relevant to it.	cspec PMID:20400964 PMID:34299313
PP3	Met	Met (Supporting): SpliceAI maximum delta 0.949 exceeds the >0.2 threshold, predicting a splice impact on this non-canonical donor-region variant.	cspec spliceai
PP4	Not assessed	Not assessed: breast cancer and ovarian serous carcinoma fit RAD51C-associated contexts but are not a highly specific single-gene phenotype.	cspec PMID:34299313
PP5	Not met	Not met: ClinVar holds only laboratory, research, and curation submissions, with no expert-panel pathogenic assertion for this exact variant.	clinvar
BA1	Not met	Not met: gnomAD v4.1 frequency of 0.000873% (14/1,602,834 alleles) is far below the >5% stand-alone benign population threshold.	cspec generic_acmg_combination_rules gnomad_v2 gnomad_v4
BS1	Not met	Not met: the observed population frequency is extremely low and shows no excess over that expected for a rare RAD51C disease-associated variant.	cspec generic_acmg_combination_rules gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: population databases show zero homozygotes but no confirmed healthy adult carrier, so BS2 cannot be evaluated.	cspec generic_acmg_combination_rules gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: the variant-specific assays demonstrate abnormal splicing rather than preserved normal function, so no benign functional evidence exists.	cspec PMID:20400964
BS4	Not assessed	Not assessed: no tested unaffected relatives lacking the variant and no family-level non-segregation analysis were available.	cspec PMID:20400964 PMID:34299313
BP1	N/A	Not applicable: BP1 concerns missense variants in genes where pathogenicity is mainly loss of function, and this is an intronic substitution.	cspec PMID:20400964 PMID:34299313
BP2	Not assessed	Not assessed: reports do not establish the variant in trans with a pathogenic allele, or in cis in a dominant disease context.	cspec PMID:20400964 PMID:34299313
BP3	N/A	Not applicable: this is an intronic single-nucleotide substitution with demonstrated exon skipping, not an in-frame deletion or insertion.	PMID:20400964
BP4	Not met	Not met: BP4 requires a SpliceAI maximum delta below 0.1, but the observed delta is 0.949.	cspec spliceai
BP5	Not assessed	Not assessed: a coexisting non-coding ATM variant was reported in one ovarian cancer patient without established pathogenicity, so no alternate diagnosis is confirmed.	PMID:34299313
BP6	Not met	Not met: ClinVar contains no expert-panel benign or likely benign assertion for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants, whereas this is an intronic +5 donor-region substitution.

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