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Variant interpretation report

RAD51C c.458G>A, p.(Gly153Asp)

NM_058216.3:c.458G>A NP_478123.1:p.(Gly153Asp) View identifiers
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.

About RAD51C

No gene-level summary was recorded for this case.

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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_058216.3:c.458G>A is extremely rare in population databases: gnomAD v2.1 allele frequency 7.95e-6 (2/251,462 alleles), gnomAD v4.1 allele frequency 1.86e-6 (3/1,614,194 alleles), both well below the 0.1% PM2 threshold. Zero homozygotes observed. Absent from gnomAD-Canada v1.0.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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; combination = 1 supporting, 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
3 / 1,614,194 alleles

gnomAD v4.1: 3 / 1,614,194 alleles. Recorded AF 1.85851e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95349e-06; MAF= 0.00080%, 2/251462 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).

SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
10 reported laboratory submissions

7 Uncertain significance · 3 Likely pathogenic.

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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

For specialists

Technical detail

ACMG/AMP criteria under ClinGen RAD51C VCEP v1.0.0, with the data and sources behind each one.

27 criteria with recorded statuses: 1 met · 17 not met · 5 not assessed · 4 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.458G>A (p.Gly153Asp) is a missense variant in RAD51C, a gene associated with autosomal dominant predisposition to breast and ovarian cancer (MONDO:0016248, MONDO:0016419) and autosomal recessive Fanconi anemia (MONDO:0019391).

The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specifications for RAD51C v1.0.0 provide no criteria-level modifications (criteria set is empty); generic ACMG/AMP 2015 criteria (PMID:25741868) were applied.

This variant is extremely rare in population databases: gnomAD v2.1 allele frequency 7.95e-6 (2/251,462 alleles), gnomAD v4.1 allele frequency 1.86e-6 (3/1,614,194 alleles), meeting PM2 at supporting strength.

In silico predictions are conflicting: REVEL score 0.635 (damaging-leaning) versus BayesDel score 0.233 (benign-leaning); SpliceAI predicts no splice impact (max delta 0.03). Neither PP3 nor BP4 is met.

ClinVar reports this variant as Uncertain significance by 7 clinical laboratories and Likely pathogenic by 3 laboratories (VariationID 185444); no expert panel consensus exists. PP5 and BP6 are not met.

Functional studies of RAD51C missense variants have been published (PMID:36099300, PMID:37253112, PMID:39299233), including saturation genome editing covering >99.5% of coding SNVs (PMID:39299233). However, NM_058216.3:c.458G>A (p.Gly153Asp) is not explicitly mentioned in available abstracts and full-text files were not available for verification. PS3 and BS3 remain not assessed pending full-text review.

No de novo reports, no segregation data, no case-control enrichment data, and no same-residue pathogenic comparator exist. All remaining assessed criteria (PS1, PS2, PS4, PM5, PM6, PP1, PP4, BS1, BS2, BS4, BP2, BP5) are not met.

With only PM2 (supporting) met and no benign criteria satisfied, this variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 framework. Definitive classification requires full-text functional data from PMID:39299233 (saturation genome editing) and/or PMID:37253112 (functional characterization of RAD51C missense VUS).

Met · 1

PM2 SupportingNM_058216.3:c.458G>A is extremely rare in population databases: gnomAD v2.1 allele frequency 7.95e-6 (2/251,462 alleles), gnomAD v4.1 allele frequency 1.86e-6 (3/1,614,194 alleles), both well below the 0.1% PM2 threshold. Zero homozygotes observed. Absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF 7.95e-6
  • 2/251
  • 462 alleles
  • 0 homozygotes
  • gnomAD v4.1: AF 1.86e-6
  • 3/1
  • 614
  • 194 alleles
  • gnomAD-Canada: absent
Sources

Not met · 17 · evaluated, threshold not reached

PS1 No evidence of a different nucleotide change at codon 153 resulting in the same amino acid substitution (p.Gly153Asp) that has been previously classified as pathogenic. Details ▾Hide ▴
Still missing
  • No known pathogenic variant producing the same amino acid change via a different nucleotide substitution was identified.
PS2 No de novo occurrence of NM_058216.3:c.458G>A has been reported in any database or publication reviewed. Details ▾Hide ▴
Still missing
  • No de novo observation reported in ClinVar
  • LOVD
  • or published literature.
PS4 No case-control study demonstrating statistically significant enrichment of NM_058216.3:c.458G>A in affected individuals versus controls has been identified. The variant is extremely rare in population databases (gnomAD v2.1 AF 7.95e-6, v4.1 AF 1.86e-6), which precludes case-control analysis. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 2/251
  • 462 alleles (AF 7.95e-6)
  • gnomAD v4.1: 3/1
  • 614
  • 194 alleles (AF 1.86e-6)
Still missing
  • No case-control cohort data available for this rare variant.
Sources
PM5 No pathogenic missense variant at the same amino acid residue (Gly153) has been identified as a comparator. Automated PM5 candidate harvesting found zero same-residue candidates. Details ▾Hide ▴
Still missing
  • No known pathogenic missense variant at codon 153.
PM6 No de novo observation of NM_058216.3:c.458G>A (assumed or confirmed) has been reported. Details ▾Hide ▴
Still missing
  • No de novo reports in ClinVar
  • LOVD
  • or published literature.
PP1 No cosegregation data are available for NM_058216.3:c.458G>A with breast or ovarian cancer in multiple affected family members. Details ▾Hide ▴
Still missing
  • No published family segregation studies including this variant.
PP3 In silico predictions are conflicting: REVEL score 0.635 (damaging-leaning, >0.5 threshold) but BayesDel score 0.233 (benign-leaning, <0.27 threshold). SpliceAI predicts no splice impact (max delta 0.03). PP3 requires multiple lines of computational evidence supporting a deleterious effect; the conflicting predictions do not meet this threshold. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.635 (damaging-leaning)
  • BayesDel score: 0.233 (benign-leaning)
  • SpliceAI max delta: 0.03 (no splice impact)
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history data specific to NM_058216.3:c.458G>A are available to assess whether the clinical presentation is highly specific for RAD51C-related disease. Details ▾Hide ▴
Still missing
  • No phenotype or family history data available for the proband(s) carrying this variant.
PP5 ClinVar reports NM_058216.3:c.458G>A as Uncertain significance by 7 clinical laboratories and Likely pathogenic by 3 laboratories. No expert panel classification exists. The predominant VUS classification and lack of expert consensus do not satisfy PP5, which requires a reputable source to have recently classified the variant as pathogenic with unavailable evidence. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 185444: VUS (7 labs)
  • Likely pathogenic (3 labs)
  • no expert panel submission
Sources
BA1 Allele frequency in gnomAD v2.1 (7.95e-6) and v4.1 (1.86e-6) is far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 7.95e-6
  • gnomAD v4.1 AF: 1.86e-6
Sources
BS1 Allele frequency in gnomAD v2.1 (7.95e-6, 0.0008%) and v4.1 (1.86e-6, 0.00019%) is far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 7.95e-6
  • gnomAD v4.1 AF: 1.86e-6
Sources
BS2 NM_058216.3:c.458G>A has not been observed in a homozygous state in gnomAD (0 homozygotes in v2.1 and v4.1) and no compound heterozygous observations in healthy adults have been reported. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 0 homozygotes
  • gnomAD v4.1: 0 homozygotes
Sources
BS4 No family segregation data are available. BS4 requires lack of segregation in affected family members — no such evidence exists for this variant. Details ▾Hide ▴
Still missing
  • No segregation data available.
BP2 No evidence that NM_058216.3:c.458G>A has been observed in trans with a known pathogenic RAD51C variant in a case of Fanconi anemia or other recessive disorder. Details ▾Hide ▴
Still missing
  • No biallelic observations of this variant with a pathogenic RAD51C variant reported.
BP4 In silico predictions are conflicting: BayesDel score 0.233 (benign-leaning, <0.27 threshold) suggests no impact, but REVEL score 0.635 (damaging-leaning, >0.5 threshold) contradicts. BP4 requires multiple lines of computational evidence suggesting no impact on gene product; only one of two predictors supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.233 (benign-leaning)
  • REVEL: 0.635 (damaging-leaning
  • conflicts with BayesDel)
  • SpliceAI max delta: 0.03 (no splice impact)
Sources
revelbayesdelspliceai ↗
BP5 No evidence that NM_058216.3:c.458G>A has been observed in a case with an alternate molecular basis for disease that would refute its pathogenicity. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data available.
BP6 ClinVar does not report NM_058216.3:c.458G>A as benign. The variant is classified as VUS by 7 clinical laboratories and Likely pathogenic by 3. No reputable source classifies this variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 185444: no benign submissions
  • 7 VUS
  • 3 LP
Sources

Not assessed · 5 · no assessment recorded

PS3 Functional studies of RAD51C missense variants exist (PMID:36099300, PMID:37253112, PMID:39299233) and the saturation genome editing study (PMID:39299233) tested >99.5% of all coding SNVs and would include p.Gly153Asp by design, but NM_058216.3:c.458G>A (p.Gly153Asp) is not explicitly mentioned in any available abstract, and full-text files are unavailable to verify the variant-specific functional result. Cannot apply PS3 without confirmed variant-level functional evidence. Details ▾Hide ▴
Evidence considered
  • PMID:39299233: saturation genome editing of >99.5% of RAD51C coding SNVs — G153D included by design but variant not named in abstract
  • PMID:37253112: functional characterization of 173 RAD51C missense VUS — variant not named in abstract snippet
  • PMID:36099300: HR-deficient mutation cluster analysis — variant not named in abstract snippet
Still missing
  • Full-text of PMID:39299233 required to extract the functional score/classification for p.Gly153Asp.
  • Full-text of PMID:37253112 required to determine if p.Gly153Asp was among the 173 missense VUS functionally characterized.
  • Full-text of PMID:36099300 required to check if G153D is in the HR-deficient mutation cluster.
Sources
360993003725311239299233
PM1 p.Gly153Asp lies within the Rad51/RecA domain (residues ~30-300), but the ClinGen HBOP VCEP for RAD51C v1.0.0 provides no PM1 specification (criteria.json is empty). Without VCEP-defined critical domains with established absence of benign missense variation, PM1 cannot be applied generically. Details ▾Hide ▴
Evidence considered
  • Residue Gly153 lies within the Rad51/RecA domain per UniProt and InterPro.
Still missing
  • No VCEP-defined PM1 domain specification for RAD51C.
  • No gnomAD missense constraint analysis confirming absence of benign missense variants in this domain.
PP2 PP2 requires a low rate of benign missense variation in the gene and that missense variants are a common disease mechanism. RAD51C has both pathogenic missense and truncating variants, but without gnomAD missense constraint metrics (Z-score, o/e ratio) or VCEP guidance, the benign missense variation rate cannot be determined for this assessment. Details ▾Hide ▴
Still missing
  • gnomAD missense constraint data (Z-score
  • o/e) for RAD51C needed to evaluate PP2 eligibility.
BS3 Functional studies exist (PMID:36099300, PMID:37253112, PMID:39299233) but NM_058216.3:c.458G>A (p.Gly153Asp) is not explicitly mentioned in any available abstract, and full-text files are unavailable. Cannot confirm or exclude a benign functional effect without variant-specific evidence. Details ▾Hide ▴
Evidence considered
  • PMID:39299233: SGE of >99.5% of coding SNVs — includes G153D by design but variant not named in abstract
  • PMID:37253112: 173 missense VUS characterized — variant not named in abstract snippet
Still missing
  • Full-text of PMID:39299233 required to determine the functional score for p.Gly153Asp.
  • Full-text of PMID:37253112 required to determine if p.Gly153Asp was tested and if the result was benign.
Sources
360993003725311239299233
PS5 PS5 requires compelling functional data from a reputable source showing a damaging effect, akin to PS3. As PS3 could not be assessed due to lack of variant-specific functional evidence in available abstracts, PS5 is also not assessed. Details ▾Hide ▴
Still missing
  • Dependent on resolution of PS3 functional evidence gap.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable — NM_058216.3:c.458G>A is a missense variant (p.Gly153Asp), not a null variant (nonsense, frameshift, canonical splice site ±1,2, initiation codon, or single/multi-exon deletion). Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 is not applicable — RAD51C is not a gene where primarily truncating variants cause disease. Both missense and truncating pathogenic variants are well-documented in RAD51C. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 is not applicable — this variant is a missense substitution, not an in-frame indel in a repetitive region without a known function. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 is not applicable — NM_058216.3:c.458G>A is a missense variant (p.Gly153Asp), not a synonymous variant with no predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
RAD51C
Transcript
NM_058216.3
Coding (HGVS c.)
NM_058216.3:c.458G>A
Protein (HGVS p.)
NP_478123.1:p.(Gly153Asp)
GRCh38
chr17:58696746 G>A
GRCh37
chr17:56774107 G>A
ClinVar
185444

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…
gnomAD v4.1 3 / 1,614,194 alleles AF 1.86e-06 · 0 homozygotes
gnomAD v2.1 2 / 251,462 alleles AF 7.95e-06 · 0 homozygotes
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,614,194 alleles · 0 hom
Admixed American1 / 60,016 1.7e-05
Remaining individuals1 / 62,510 1.6e-05
European (non-Finnish)1 / 1,180,028 8.5e-07
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 8e-06 · 2 / 251,462 alleles · 0 hom
Admixed American1 / 34,592 2.9e-05
European (non-Finnish)1 / 113,750 8.8e-06
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.85851e-06; MAF= 0.00019%, 3/1614194 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66622e-05; MAF= 0.00167%, 1/60016 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95349e-06; MAF= 0.00080%, 2/251462 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -46 bp
0.010
SpliceAI acceptor gainat -53 bp
0.010
SpliceAI donor lossat -1 bp
0.030
SpliceAI donor gainat +113 bp
0.010
Pangolin splice lossmagnitude shown
-0.060
Pangolin splice gain
0.040

Other predictors

REVEL
0.635
BayesDel
0.233

How the predictions were used

PP3 In silico predictions are conflicting: REVEL score 0.635 (damaging-leaning, >0.5 threshold) but BayesDel score 0.233 (benign-leaning, <0.27 threshold). SpliceAI predicts no splice impact (max delta 0.03). PP3 requires multiple lines of computational evidence supporting a deleterious effect; the conflicting predictions do not meet this threshold. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.635 (damaging-leaning)
  • BayesDel score: 0.233 (benign-leaning)
  • SpliceAI max delta: 0.03 (no splice impact)
Sources
revelbayesdelspliceai ↗
BP4 In silico predictions are conflicting: BayesDel score 0.233 (benign-leaning, <0.27 threshold) suggests no impact, but REVEL score 0.635 (damaging-leaning, >0.5 threshold) contradicts. BP4 requires multiple lines of computational evidence suggesting no impact on gene product; only one of two predictors supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.233 (benign-leaning)
  • REVEL: 0.635 (damaging-leaning
  • conflicts with BayesDel)
  • SpliceAI max delta: 0.03 (no splice impact)
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 is not applicable — NM_058216.3:c.458G>A is a missense variant (p.Gly153Asp), not a synonymous variant with no predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.635. BayesDel score = 0.233494.

9 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

  • RAD51C germline mutations in breast and ovarian cancer cases from high-risk families.
    Clague J et al. · 2011
    No paper-specific finding is recorded.
    PMID 21980511 ↗
  • Germline mutations in RAD51C in Jewish high cancer risk families.
    Kushnir A et al. · 2012
    No paper-specific finding is recorded.
    PMID 23117857 ↗
  • Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
    No paper-specific finding is recorded.
    PMID 23918944 ↗
  • 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.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Homologous recombination-deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants.
    Prakash R et al. · 2022
    No paper-specific finding is recorded.
    PMID 36099300 ↗
  • Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.
    Hu C et al. · 2023
    No paper-specific finding is recorded.
    PMID 37253112 ↗
  • High-resolution functional mapping of RAD51C by saturation genome editing.
    Olvera-León R et al. · 2024
    No paper-specific finding is recorded.
    PMID 39299233 ↗
  • American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
    No paper-specific finding is recorded.
    PMID 12692171 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

All source links

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= 1.85851e-06; MAF= 0.00019%, 3/1614194 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66622e-05; MAF= 0.00167%, 1/60016 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95349e-06; MAF= 0.00080%, 2/251462 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely pathogenic (3 clinical laboratories). (ClinVarID = 185444)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.635. BayesDel score = 0.233494.

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.