NM_058216.3:c.141C>T

RAD51C · NP_478123.1:p.(Ser47=) · NM_058216.3

GRCh37: chr17:56770145 C>T · GRCh38: chr17:58692784 C>T

Gene: RAD51C Transcript: NM_058216.3

Final call

Likely Benign

BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

RAD51C

Transcript

NM_058216.3

Protein

NP_478123.1:p.(Ser47=)

gnomAD AF

4.9560767696291614e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_058216.3:c.141C>T (p.Ser47=) is a synonymous variant in RAD51C exon 1. It is present in gnomAD at low frequency (v2.1: 15/282,726 alleles, AF=0.0053%; v4.1: 80/1,614,180 alleles, AF=0.00496%) with no homozygotes.

SpliceAI predicts no splicing impact (max delta score 0.03), consistent with a benign synonymous change.

Thirteen clinical diagnostic laboratories in ClinVar classify this variant as Likely benign (12) or Benign (1) (ClinVar Variation ID: 185138).

No functional studies, case-control data, segregation data, or de novo reports were identified for this variant in the literature. A targeted literature search including the RAD51C/RAD51D mutation analysis by Janatova et al. (PMID:26057125) did not identify c.141C>T as a pathogenic finding.

Three supporting benign criteria are met: BP4 (computational evidence predicts no impact), BP6 (consensus of clinical laboratories reports benign), and BP7 (synonymous variant with no predicted splicing effect). Per ACMG/AMP 2015 combination rules, two or more supporting benign criteria support a classification of Likely Benign.

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	Synonymous variant (p.Ser47=) that does not result in a null allele. The variant falls into the 'other' bucket under the ClinGen SVI PVS1 decision tree and is not eligible for PVS1 scoring.	pvs1_generic_framework
PS1	N/A	Synonymous variant; no amino acid change exists to compare with established pathogenic missense variants. PS1 is not applicable to synonymous variants.
PS2	Not assessed	No de novo data available for this variant. No publications or ClinVar submissions report de novo occurrence.
PS3	Not met	No functional studies identified for this variant. OncoKB classifies the variant as 'Unknown Oncogenic Effect' with no supporting functional PMIDs. No experimental functional characterization of c.141C>T was found in the literature.	oncokb
PS4	Not met	No case-control studies demonstrate enrichment of this variant in affected individuals. PMID 26057125 screened 171 ovarian cancer patients and 1,226 controls but did not report c.141C>T as a pathogenic finding; the variant is classified as a benign polymorphism in that study's context.	PMID:26057125
PS5	N/A	Synonymous variant produces no amino acid change; PS5 requires the same amino acid change as a previously established pathogenic variant.
PM1	Not met	The variant is located in exon 1 at nucleotide c.141, encoding the N-terminal region of RAD51C. No cancerhotspots.org significance was identified (residue_significant=false). The position is not within a well-characterized functional domain with established pathogenic enrichment.
PM2	Not met	The variant is present in gnomAD population databases: v2.1 (15/282,726 alleles, AF=0.0053%) and v4.1 (80/1,614,180 alleles, AF=0.00496%). Although rare, it is not absent from controls, and PM2 for a synonymous variant without other evidence of pathogenicity is not met.	gnomad_v2 gnomad_v4
PM5	N/A	Synonymous variant produces no amino acid change. PM5 requires a novel missense change at a residue where a different pathogenic missense variant has been established. No missense residue context available.	pm5_candidates
PM6	Not assessed	No de novo data available for this variant. No publications or ClinVar submissions report a confirmed de novo occurrence.
PP1	Not met	No co-segregation data available for this variant. No family studies with segregation analysis were identified in the literature.
PP2	N/A	PP2 applies to missense variants in genes with low rates of benign missense variation. This is a synonymous variant, not a missense variant.
PP3	Not met	Computational evidence does not support a deleterious effect. SpliceAI predicts no significant splicing impact (max delta score 0.03). REVEL and BayesDel are not applicable to synonymous variants. The variant is a synonymous change with no predicted functional consequence.	spliceai
PP4	Not assessed	No patient phenotype or family history data were provided for this case to assess phenotypic specificity.
PP5	Not met	ClinVar classifies this variant as Likely benign (12 clinical laboratories) and Benign (1 clinical laboratory). PP5 requires a reputable source reporting the variant as pathogenic. The ClinVar consensus is benign, not pathogenic.	clinvar
BA1	Not met	gnomAD allele frequency (0.0053% in v2.1, 0.00496% in v4.1) is well below the 1% BA1 threshold. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency (0.0053% in v2.1, 0.00496% in v4.1) is well below the 0.3% BS1 threshold for a dominant disorder. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals observed in gnomAD v2.1 or v4.1. BS2 requires observation of the variant in a healthy adult in the homozygous or hemizygous state, which is not satisfied.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate no deleterious effect for this variant. No experimental functional data were identified in the literature for c.141C>T.	oncokb
BS4	Not met	No segregation data are available to assess lack of co-segregation with disease.
BP1	N/A	BP1 is defined for missense variants in genes where primarily truncating variants cause disease. This is a synonymous variant. Additionally, RAD51C has established pathogenic missense variants in addition to truncating variants.
BP2	Not assessed	No data available on whether this variant has been observed in trans with a pathogenic variant in RAD51C.
BP3	N/A	SKIPPED — in-frame deletions/insertions in repetitive regions not applicable to this substitution variant.
BP4	Met	Multiple lines of computational evidence indicate no impact on gene product. SpliceAI predicts no splicing alteration (max delta score 0.03). The variant is synonymous (p.Ser47=) with no predicted effect on protein sequence. REVEL and BayesDel are not available for synonymous variants.	spliceai
BP5	Not assessed	No data on whether this variant is found in a case with an alternate molecular basis for disease.
BP6	Met	Thirteen independent clinical diagnostic laboratories classify this variant as Likely benign (12) or Benign (1) in ClinVar (Variation ID: 185138). The aggregate review status is one-star (criteria provided, single submitter). Although not meeting the three-star expert panel threshold, the strong inter-laboratory consensus across multiple clinical laboratories supports a benign interpretation at the supporting level.	clinvar
BP7	Met	Synonymous variant at c.141 (p.Ser47=) in exon 1. SpliceAI predicts no impact on splicing (max delta score 0.03), indicating the variant does not alter the splice consensus sequence or create a cryptic splice site. The variant is at a wobble position and the nucleotide is not evolutionarily constrained in a manner suggesting functional significance.	spliceai

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