About RAD51C
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD51C c.923C>G, p.(Ala308Gly)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen RAD51C VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is extremely rare in population databases. gnomAD v4.1 reports an allele frequency of 4.959e-06 (8/1,613,092 alleles; 0 homozygotes; grpmax FAF=5.281e-05), well below the 0.1% threshold for PM2. gnomAD v2.1 reports 1/251,378 alleles (AF=3.978e-06). Absent from gnomAD-Canada.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.262 (below damaging threshold), BayesDel score is -0.252908 (benign prediction), and SpliceAI max delta is 0.08 (no predicted splicing impact). The consensus of in silico predictors supports a benign effect.
Recorded classification: Uncertain significance
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAD51C Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
8 / 1,613,092 alleles
gnomAD v4.1: 8 / 1,613,092 alleles. Recorded AF 4.95942e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97807e-06; MAF= 0.00040%, 1/251378 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15309e-05; MAF= 0.00615%, 1/16252 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.080 maximum delta
Recorded SpliceAI maximum delta score: 0.080. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
8 reported laboratory submissions
7 Uncertain significance · 1 Benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RAD51C, a DNA repair protein, is altered by mutation or deletion in certain breast cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV106470523, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen RAD51C VCEP v1.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 9 not met · 13 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_058216.3:c.923C>G (p.Ala308Gly) is a missense variant in exon 7 of RAD51C, a gene associated with autosomal dominant predisposition to breast and ovarian cancer and autosomal recessive Fanconi anemia.
This variant is extremely rare in population databases: gnomAD v4.1 reports 8 of 1,613,092 alleles (AF=4.959e-06, 0 homozygotes), and gnomAD v2.1 reports 1 of 251,378 alleles (AF=3.978e-06). The variant is absent from gnomAD-Canada.
Multiple in silico predictors consistently suggest a benign effect: REVEL score 0.262 (below damaging threshold), BayesDel -0.252908 (benign prediction), and SpliceAI max delta 0.08 (no splicing impact).
ClinVar records this variant as Uncertain significance by 7 clinical laboratories and Benign by 1 laboratory (Variation ID 187133), all with single-submitter review status and no expert panel classification.
No verified functional studies demonstrate a damaging effect. A functional study reportedly showing wild-type-like activity (PMID:33409066) could not be verified as full-text was unavailable.
Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): PM2 (supporting pathogenic) and BP4 (supporting benign) are met. All other criteria are either not met, not assessed, or not applicable. The net classification is Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is extremely rare in population databases. gnomAD v4.1 reports an allele frequency of 4.959e-06 (8/1,613,092 alleles; 0 homozygotes; grpmax FAF=5.281e-05), well below the 0.1% threshold for PM2. gnomAD v2.1 reports 1/251,378 alleles (AF=3.978e-06). Absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=3.978e-06 (1/251
- 378 alleles
- 0 homozygotes)
- gnomAD v4.1: AF=4.959e-06 (8/1
- 613
- 092 alleles
- gnomAD-Canada: absent
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.262 (below damaging threshold), BayesDel score is -0.252908 (benign prediction), and SpliceAI max delta is 0.08 (no predicted splicing impact). The consensus of in silico predictors supports a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.262 (below 0.5 threshold
- suggesting no damaging effect)
- BayesDel: -0.252908 (benign prediction)
- SpliceAI max delta: 0.08 (no splicing impact)
Sources
Not met · 9 · evaluated, threshold not reached
PS3 No verified functional evidence demonstrates a damaging effect for this variant. The exploratory literature search identified one study (Ahlborn et al. 2021, PMID:33409066) that reportedly found wild-type-like activity, but full-text is not available for verification; even if taken at face value, the reported finding is neutral-to-benign, not damaging. Details ▾Hide ▴
Evidence considered
- No verified functional study shows a damaging effect on protein function.
Still missing
- PMID:33409066 (Ahlborn et al. 2021) reportedly evaluated p.Ala308Gly in functional assays but full-text was not available for verification. Results reportedly showed wild-type-like activity.
PS4 Insufficient case-control data to meet PS4. The exploratory search identified Sun et al. 2018 (PMID:30257646) reporting this variant in 1 of 1,090 breast cancer cases and 0 of 1,036 controls, but the paper is not available for full-text verification. Even if verified, the single observation does not achieve statistical significance required for PS4. Details ▾Hide ▴
Evidence considered
- Insufficient case-control data
- 1 case observation insufficient for statistical enrichment.
Still missing
- Larger case-control datasets (e.g.
- ENIGMA/CIMBA consortium) needed to assess enrichment.
PM1 This variant does not lie in a statistically significant mutational hotspot (Cancer Hotspots negative). While p.Ala308 resides within the RecA domain (aa 1-376), RAD51C lacks a VCEP-defined or well-established critical functional domain specification for PM1 under generic ACMG/AMP rules. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: no significant hotspot. No VCEP-defined PM1 domain for RAD51C available.
Still missing
- No curated domain-level pathogenic enrichment data available for RAD51C.
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.262 (below 0.5 damaging threshold), BayesDel score is -0.252908 (strongly in benign range), and SpliceAI max delta is 0.08 (no predicted splicing impact). All in silico tools consistently predict a benign or neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.262 (below damaging threshold of 0.5)
- BayesDel: -0.252908 (benign prediction)
- SpliceAI max delta: 0.08 (no splicing impact)
Sources
PP5 No reputable source has classified this variant as pathogenic. ClinVar reports this variant as Uncertain significance (7 clinical laboratories) and Benign (1 clinical laboratory), all with single-submitter review status. No expert panel or practice guideline has asserted pathogenicity. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 187133: 7 labs report VUS
- 1 lab reports Benign
- all single-submitter status
- No expert panel or reputable source classifies as pathogenic
Sources
BA1 Allele frequency in gnomAD v4.1 is 4.959e-06 (0.0005%), far below the 1% threshold required for BA1. Details ▾Hide ▴
BS1 Allele frequency in gnomAD v4.1 is 4.959e-06 (0.0005%), far below the 0.3% threshold required for BS1. Details ▾Hide ▴
BP1 BP1 is not applicable to RAD51C. Both missense and truncating variants are established disease mechanisms in RAD51C (heterozygous for breast/ovarian cancer, biallelic for Fanconi anemia). The gene is not one where primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- RAD51C has both missense and truncating pathogenic variants
- missense disease mechanism is well-established.
Sources
pvs1_gene_context
BP6 No reputable source has classified this variant as benign with supporting evidence that is unavailable for review. The single Benign classification in ClinVar is from a single submitter without expert panel status and does not meet the BP6 threshold for a reputable source. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 lab classifies as Benign (single submitter
- not expert panel). Insufficient for BP6.
Sources
Not assessed · 13 · no assessment recorded
PS1 No known pathogenic variant at the same amino acid position (Ala308) with a different nucleotide change was identified in ClinVar or the literature. Unable to assess PS1 without a comparator. Details ▾Hide ▴
Still missing
- No pathogenic variant at codon 308 identified as a comparator.
PS2 No de novo observations were identified in ClinVar, literature, or de novo databases. Exploratory search confirmed absence of de novo reports for this variant. Details ▾Hide ▴
Still missing
- No de novo observations available.
PM5 No same-residue pathogenic comparator variants were identified. PM5 candidate harvesting returned zero candidates at codon 308. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned no same-residue comparator variants.
Still missing
- No known pathogenic missense variant at codon 308 available for comparison.
PM6 No de novo observations with confirmed maternity and paternity were identified for this variant. Details ▾Hide ▴
Still missing
- No de novo observations available.
PP1 No cosegregation data are available for this variant. Details ▾Hide ▴
Still missing
- No family studies or cosegregation data published.
PP2 While missense variants are a known disease mechanism in RAD51C, PP2 additionally requires demonstration that the gene has a low rate of benign missense variation (e.g., high missense Z-score). No constraint data or gene-level missense intolerance metric was available in the evidence to support this criterion. Details ▾Hide ▴
Evidence considered
- RAD51C missense variants are a known mechanism
- but no constraint data available to assess rate of benign missense variation.
Still missing
- No gnomAD missense constraint (Z-score) data provided for RAD51C.
PP4 No specific phenotypic data are available for the individual(s) carrying this variant to assess whether the phenotype is highly specific for RAD51C-related disease. Details ▾Hide ▴
Still missing
- No patient phenotype data available.
BS2 No data are available regarding the observation of this variant in healthy adults without disease to rule out a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No data on unaffected carriers at advanced age.
BS3 The exploratory literature search identified Ahlborn et al. 2021 (PMID:33409066) as reporting wild-type-like functional activity for p.Ala308Gly in homologous recombination, RAD51 foci formation, and MMC sensitivity assays. However, the full-text of this paper was not available for verification and the paper is not in the source registry. Without verified full-text confirming the assays are well-established and the variant is directly evaluated, BS3 cannot be applied. Details ▾Hide ▴
Evidence considered
- PMID:33409066 reportedly shows wild-type-like function but full-text not available for verification.
Still missing
- Full-text of PMID:33409066 needed to verify functional assay results for p.Ala308Gly and confirm assays meet ClinGen SVI functional evidence standards for BS3.
BS4 No data are available regarding lack of segregation with disease or observation of this variant in trans with a known pathogenic RAD51C variant. Details ▾Hide ▴
Still missing
- No cosegregation data or cis/trans phase information available.
BP2 No observation of this variant in cis with a known pathogenic RAD51C variant has been reported. Details ▾Hide ▴
Still missing
- No phase information available from clinical testing laboratories.
BP5 No observation of this variant in an individual with an alternate molecular basis for disease has been reported. Details ▾Hide ▴
Still missing
- No data on co-occurrence with alternate disease explanation.
PS5 No alternate variant at the same nucleotide position with stronger evidence of pathogenicity was identified. Details ▾Hide ▴
Still missing
- No alternate pathogenic variant at c.923 identified.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_058216.3:c.923C>G is a missense variant (p.Ala308Gly) and does not fall into a null-variant bucket (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or large genomic deletion). Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
PM3 N/ASkipped per instruction: trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per instruction: trivially not applicable to a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_058216.3:c.923C>G is a missense variant (p.Ala308Gly) and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is specific to synonymous variants.
Identifiers
- Gene
- RAD51C
- Transcript
- NM_058216.3
- Coding (HGVS c.)
- NM_058216.3:c.923C>G
- Protein (HGVS p.)
- NP_478123.1:p.(Ala308Gly)
- GRCh38
- chr17:58724058 C>G
- GRCh37
- chr17:56801419 C>G
- ClinVar
- 187133
- COSMIC
- COSV106470523
Gene diagram
Every interpreted variant in RAD51C, mapped onto the exon structure of NM_058216.3. Select a row to find it on the plot.
RAD51CNM_058216.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in RAD51C
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
8 / 1,613,092 alleles
AF 4.96e-06 · 0 homozygotes · FAF 5.28e-05
gnomAD v2.1
1 / 251,378 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5e-06 · 8 / 1,613,092 alleles · 0 hom · FAF 5.3e-05
| African/African American8 / 74,886 | 0.00011 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 4e-06 · 1 / 251,378 alleles · 0 hom
| African/African American1 / 16,252 | 6.2e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.95942e-06; MAF= 0.00050%, 8/1613092 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000106829; MAF= 0.01068%, 8/74886 alleles, homozygotes = 0); grpmax FAF= 5.281e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97807e-06; MAF= 0.00040%, 1/251378 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15309e-05; MAF= 0.00615%, 1/16252 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.262
- BayesDel
- -0.253
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.262 (below damaging threshold), BayesDel score is -0.252908 (benign prediction), and SpliceAI max delta is 0.08 (no predicted splicing impact). The consensus of in silico predictors supports a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.262 (below 0.5 threshold
- suggesting no damaging effect)
- BayesDel: -0.252908 (benign prediction)
- SpliceAI max delta: 0.08 (no splicing impact)
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.262 (below 0.5 damaging threshold), BayesDel score is -0.252908 (strongly in benign range), and SpliceAI max delta is 0.08 (no predicted splicing impact). All in silico tools consistently predict a benign or neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.262 (below damaging threshold of 0.5)
- BayesDel: -0.252908 (benign prediction)
- SpliceAI max delta: 0.08 (no splicing impact)
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_058216.3:c.923C>G is a missense variant (p.Ala308Gly) and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is specific to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.262. BayesDel score = -0.252908.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 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.Richards S et al. · 2015This is the ACMG/AMP 2015 standards and guidelines for sequence variant interpretation. The paper defines the generic classification framework and combination rules but does not evaluate or mention NM_058216.3:c.923C>G or any specific RAD51C variant.Does not name this variant
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi I et al. · 2016Karbassi et al. describe a standardized DNA variant scoring system (Sherloc precursor). The paper provides a rules-based scoring framework for variant classification but does not evaluate or mention NM_058216.3:c.923C>G or any RAD51C variant specifically.Does not name this variant
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PMID 32832836 ↗Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.Matejcic M et al. · 2020Matejcic et al. evaluated pathogenic variants in 19 cancer predisposition genes (including RAD51C) for prostate cancer risk in men of African ancestry. The paper describes RAD51C variants at the gene level but does not mention NM_058216.3:c.923C>G or p.Ala308Gly.Does not name this variant
-
PMID 20301575 ↗Fanconi Anemia.Adam MP et al. · 1993GeneReviews entry for Fanconi Anemia. Provides an overview of Fanconi anemia genes including RAD51C but does not evaluate or mention NM_058216.3:c.923C>G.Does not name this variant
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PMID 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.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. This is a clinical practice guideline that does not evaluate or mention specific RAD51C variants.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Nykamp et al. describe the Sherloc variant classification system, a refinement of ACMG/AMP criteria. The paper provides a general classification framework and does not evaluate or mention NM_058216.3:c.923C>G.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
8 / 1,613,092 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.080
Open source ↗
ClinVar
7 Uncertain significance · 1 Benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1535377178
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/187133/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-56801419-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-58724058-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-58724058-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_058216.3%3Ac.923C…
- OncoKB ↗www.oncokb.org/gene/RAD51C/A308G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=129865519
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.95942e-06; MAF= 0.00050%, 8/1613092 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000106829; MAF= 0.01068%, 8/74886 alleles, homozygotes = 0); grpmax FAF= 5.281e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97807e-06; MAF= 0.00040%, 1/251378 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15309e-05; MAF= 0.00615%, 1/16252 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 187133)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.262. BayesDel score = -0.252908.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RAD51C, a DNA repair protein, is altered by mutation or deletion in certain breast cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV106470523, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.