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.1 SpliceAI predicts no splicing impact (max delta score 0.03), consistent with a benign synonymous change.2 Thirteen clinical diagnostic laboratories in ClinVar classify this variant as Likely benign (12) or Benign (1) (ClinVar Variation ID: 185138).3 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.4 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.5
RAD51C
Final classification
Likely Benign
RAD51C c.141C>T · p.Ser47=
RAD51C
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.
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAD51C Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 3 supporting benign, which maps to Likely Benign.
Classification rationale
BP4BP6BP7
Likely Benign
RAD51C c.141C>T
BP4 + BP6 + BP7
→
Likely Benign
5
generic_acmg_combination_rules
Gene diagram
· NM_058216.3 · variants mapped to exon structure
RAD51C
NM_058216.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
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 max delta 0.03: no predicted splicing impact. Synonymous variant with no amino acid changeconsistent with benign computational profile.
✓
BP6
supporting
Benign
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 Variation ID 185138: Likely benign in 12 clinical laboratoriesBenign in 1 clinical laboratory. Submitters include Quest DiagnosticsAmbry Genetics
✓
BP7
supporting
Benign
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 max delta 0.03: no predicted donor/acceptor gain or loss. Synonymous substitution at wobble position with no predicted effect on splicing.
Assessed · not applied
Pathogenic
PS2
No de novo data available for this variant.
PS3
No functional studies identified for this variant.
PS4
No case-control studies demonstrate enrichment of this variant in affected individuals.
PM1
The variant is located in exon 1 at nucleotide c.141, encoding the N-terminal region of RAD51C.
PM2
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%).
PM6
No de novo data available for this variant.
PP1
No co-segregation data available for this variant.
PP3
Computational evidence does not support a deleterious effect.
PP4
No patient phenotype or family history data were provided for this case to assess phenotypic specificity.
PP5
ClinVar classifies this variant as Likely benign (12 clinical laboratories) and Benign (1 clinical laboratory).
Benign
BA1
gnomAD allele frequency (0.0053% in v2.1, 0.00496% in v4.1) is well below the 1% BA1 threshold.
BS1
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.
BS2
No homozygous individuals observed in gnomAD v2.1 or v4.1.
BS3
No well-established functional studies demonstrate no deleterious effect for this variant.
BS4
No segregation data are available to assess lack of co-segregation with disease.
BP2
No data available on whether this variant has been observed in trans with a pathogenic variant in RAD51C.
BP5
No data on whether this variant is found in a case with an alternate molecular basis for disease.
N/A · 6
PVS1 · PS1 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.95608e-05; MAF= 0.00496%, 80/1614180 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00082481; MAF= 0.08248%, 5/6062 alleles, homozygotes = 0); grpmax FAF= 0.00032406.
v2.1
This variant is present in gnomAD v2.1 (AF= 5.30549e-05; MAF= 0.00531%, 15/282726 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000195976; MAF= 0.01960%, 6/30616 alleles, homozygotes = 0); grpmax FAF= 8.51e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.005%
· 80 / 1,614,180
0 hom · FAF 0.032%
0 hom · FAF 0.032%
Middle Eastern 5 / 6,062 |
0.082% |
South Asian 16 / 91,082 |
0.018% |
Remaining individuals 5 / 62,512 |
0.008% |
European (non-Finnish) 53 / 1,180,026 |
0.0045% |
African/African American 1 / 75,074 |
0.0013% |
+ 5 not observed (Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0053%
· 15 / 282,726
0 hom · FAF 0.0085%
0 hom · FAF 0.0085%
South Asian 6 / 30,616 |
0.02% |
European (non-Finnish) 8 / 129,046 |
0.0062% |
African/African American 1 / 24,966 |
0.004% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (12 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 185138)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 9 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
23188549 ↗
NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
CLINVAR
24493721 ↗
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
CLINVAR
25356965 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
26057125 ↗
Mutation Analysis of the RAD51C and RAD51D Genes in High-Risk Ovarian Cancer Patients and Families from the Czech Republic.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR