About RAD51C
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD51C c.30G>T, p.(Met10Ile)
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
NM_058216.3:c.30G>T is present at extremely low frequency in population databases: gnomAD v2.1 (1/251,450 alleles, AF=3.98e-6), gnomAD v4.1 (1/1,614,238 alleles, AF=6.19e-7), and absent from gnomAD-Canada. These frequencies are well below the 0.1% PM2 threshold for a rare disease variant.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple in silico predictors suggest a benign effect. BayesDel score is -0.112 (negative, consistent with benign), REVEL score is 0.24 (below pathogenic threshold of 0.5), and SpliceAI max delta is 0.04 (no splicing impact). Three independent computational tools converge on a non-damaging prediction.
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 benign; 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
1 / 1,614,238 alleles
gnomAD v4.1: 1 / 1,614,238 alleles. Recorded AF 6.19487e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97693e-06; MAF= 0.00040%, 1/251450 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79214e-06; MAF= 0.00088%, 1/113738 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
3 Uncertain significance.
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.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen RAD51C VCEP v1.0.0, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 9 not met · 12 not assessed · 3 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.30G>T (p.Met10Ile) is a missense variant in exon 1 of RAD51C, a gene associated with autosomal dominant hereditary breast and ovarian cancer and autosomal recessive Fanconi anemia.
This variant is present at extremely low frequency in population databases: gnomAD v2.1 (1/251,450 alleles, AF=3.98e-6), gnomAD v4.1 (1/1,614,238 alleles, AF=6.19e-7), and absent from gnomAD-Canada, meeting PM2 at supporting level.
Multiple in silico predictors suggest a benign effect: REVEL score is 0.24 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.112 (consistent with benign), and SpliceAI predicts no splicing impact (max delta=0.04). This meets BP4 at supporting benign level.
This variant has been reported in ClinVar as Uncertain significance by three clinical laboratories (ClinVar Variation ID: 538784). No expert panel has classified this variant as pathogenic or benign.
The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel has published a specification document for RAD51C (Version 1.0.0), but the criterion-level rules are not yet structured for automated application. The generic ACMG/AMP 2015 framework was used as fallback.
No variant-specific functional studies, segregation data, de novo reports, or case-control analyses were identified for this exact variant. The comprehensive RAD51C functional screen by Hu et al. 2023 (PMID:37253112) tested 173 missense variants but did not include p.Met10Ile.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is indeterminate. This variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 combination rules.
No criteria match.
Met · 2
PM2 SupportingNM_058216.3:c.30G>T is present at extremely low frequency in population databases: gnomAD v2.1 (1/251,450 alleles, AF=3.98e-6), gnomAD v4.1 (1/1,614,238 alleles, AF=6.19e-7), and absent from gnomAD-Canada. These frequencies are well below the 0.1% PM2 threshold for a rare disease variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/251
- 450 (AF=0.0004%)
- gnomAD v4.1: 1/1
- 614
- 238 (AF=0.00006%)
- gnomAD-Canada: absent
Sources
BP4 SupportingMultiple in silico predictors suggest a benign effect. BayesDel score is -0.112 (negative, consistent with benign), REVEL score is 0.24 (below pathogenic threshold of 0.5), and SpliceAI max delta is 0.04 (no splicing impact). Three independent computational tools converge on a non-damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL=0.24 (below pathogenic threshold)
- BayesDel=-0.112 (benign direction)
- SpliceAI max delta=0.04 (no splice impact)
Sources
Not met · 9 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 10 producing the same amino acid change (Met10Ile) has been established as pathogenic. The alternative nucleotide substitutions that would also yield Met10Ile (c.30G>C, c.30G>A) have no pathogenic classification in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No pathogenic same-AA-different-nucleotide variant identified at Met10
Sources
PM1 Met10 lies in the N-terminal region of RAD51C (residue 1–83), which is structurally flexible and not part of any known critical functional domain. The pathogenic missense hotspot identified by Hu et al. 2023 maps to residues 125–168 (Walker A P-loop / ATP-binding region). Residue 10 is far from this hotspot and not in a functionally constrained domain. Details ▾Hide ▴
Evidence considered
- Hotspot analysis negative
- residue 10 not in Walker A P-loop (125-168) or any known functional domain
Sources
PP2 PP2 applies to genes with a low rate of benign missense variation where missense is a common disease mechanism. RAD51C has a substantial number of benign missense variants in gnomAD and does not meet the low-benign-missense-rate threshold. The Hu et al. 2023 study identified 135 neutral missense variants out of 173 tested, confirming that many RAD51C missense variants are functionally benign. Details ▾Hide ▴
Evidence considered
- RAD51C has a high proportion of functionally neutral missense variants (135/173 in Hu et al. 2023)
Sources
PP3 In silico predictors do not support a damaging effect. REVEL score is 0.24 (below typical pathogenic threshold of 0.5), BayesDel score is -0.112 (negative, suggesting benign), and SpliceAI max delta is 0.04 (no predicted splicing impact). Multiple lines of computational evidence do not support pathogenicity. Details ▾Hide ▴
PP5 No reputable source has classified this variant as pathogenic. ClinVar reports this variant as Uncertain significance (3 clinical laboratories, criteria provided, single submitter). No expert panel has classified it as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- 3 submitters
- no expert panel pathogenic classification
Sources
BA1 The variant has an allele frequency far below the BA1 threshold (>1%). gnomAD v2.1 AF=0.0004%, gnomAD v4.1 AF=0.00006%. This variant is exceedingly rare, not common. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=3.98e-6
- v4.1 AF=6.19e-7
- both far below 1%
Sources
BS1 The variant frequency is far below the BS1 threshold (>0.3% for non-VCEP). gnomAD v2.1 AF=0.0004%, v4.1 AF=0.00006%. The variant is too rare to meet BS1. Details ▾Hide ▴
Evidence considered
- gnomAD maximum population AF=0.00088% (NFE)
- far below 0.3% threshold
Sources
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. RAD51C has well-established pathogenic missense variants: Hu et al. 2023 identified 30 functionally deleterious missense variants in RAD51C, demonstrating that missense changes are a known pathogenic mechanism in this gene. BP1 does not apply. Details ▾Hide ▴
Evidence considered
- RAD51C has 30 known deleterious missense variants
- missense is an established pathogenic mechanism
Sources
BP6 No reputable source has classified this variant as benign. ClinVar reports this variant as Uncertain significance. BP6 requires a reputable source to have reported the variant as benign without access to the primary evidence. Details ▾Hide ▴
Not assessed · 12 · no assessment recorded
PS2 No de novo data available for this variant. No family studies or parent-of-origin testing reported in ClinVar or the literature. Details ▾Hide ▴
Still missing
- No de novo testing data available
PS3 No variant-specific functional studies of NM_058216.3:c.30G>T (p.Met10Ile) were identified. The comprehensive RAD51C functional screen by Hu et al. 2023 (PMID:37253112) tested 173 missense variants but did not include M10I. No other functional assay data were found in the literature or OncoKB. Details ▾Hide ▴
Evidence considered
- PMID:37253112 did not include M10I among 173 tested missense variants
- OncoKB reports Unknown Oncogenic Effect
Still missing
- No functional assay data for this specific variant
PS4 No variant-specific case-control association data available. The Hu et al. 2023 case-control analysis of RAD51C deleterious missense variants did not include M10I. The Canadian cohort study (PMID:34326862) discussed RAD51C pathogenic variants at the gene level but did not report this specific variant. Details ▾Hide ▴
Evidence considered
- No case-control data for M10I
Still missing
- No case-control or enrichment data for this variant
PM6 No de novo data available. PM6 requires confirmed de novo occurrence with maternity and paternity confirmed, which has not been reported for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data available
PP1 No co-segregation data available. No family studies reporting segregation of this variant with disease in multiple affected family members were identified. Details ▾Hide ▴
Still missing
- No segregation data available
PP4 No patient-specific phenotype or family history data are available for this variant. The ClinVar submissions do not include detailed phenotype information. Details ▾Hide ▴
Still missing
- No patient phenotype data available
BS2 No observation of this variant in a homozygous state or in trans with a pathogenic variant in a healthy adult. gnomAD reports 0 homozygotes, and no such observations were identified in the literature. Details ▾Hide ▴
Evidence considered
- gnomAD homozygotes = 0
Still missing
- No data on healthy adult homozygotes or trans configurations
BS3 No variant-specific functional studies demonstrating no damaging effect were identified. The Hu et al. 2023 functional screen (PMID:37253112) did not include M10I. OncoKB reports Unknown Oncogenic Effect with no reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- No functional study including M10I identified
- OncoKB: Unknown Oncogenic Effect
Still missing
- No functional assay data for this specific variant
BS4 No segregation data are available. No family studies reporting lack of segregation of this variant with disease were identified. Details ▾Hide ▴
Still missing
- No segregation data available
BP2 No observation of this variant in trans with a known pathogenic variant in a healthy individual has been reported. RAD51C is associated with autosomal dominant hereditary breast/ovarian cancer; observation in trans with a pathogenic variant without disease would support a benign interpretation, but no such data exist. Details ▾Hide ▴
Still missing
- No trans-configuration data available
BP5 No data available on whether this variant has been observed in a case with an alternate molecular basis for disease. No reports of co-occurrence with a known pathogenic variant in the same gene or another gene explaining the phenotype. Details ▾Hide ▴
Still missing
- No co-occurrence data with other pathogenic variants
PS5 No pathogenic variant has been established at the Met10 residue position of RAD51C. No different missense change at Met10 is classified as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_058216.3:c.30G>T is a missense variant (p.Met10Ile) in exon 1. It does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Under both the ClinGen SVI PVS1 framework (PMC6185798) and generic ACMG/AMP rules, PVS1 is not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant_bucket=other
- apply_generic_pvs1_framework=false
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/ANo candidate comparator variants at the same residue (Met10) with a different pathogenic missense change were identified. The automated PM5 candidate harvest found zero same-residue candidates, and manual review confirmed no known pathogenic variants at this position. Details ▾Hide ▴
Evidence considered
- Zero same-residue pathogenic comparator candidates identified
Sources
pm5_candidatesclinvar ↗
BP7 N/ANM_058216.3:c.30G>T is a missense variant (p.Met10Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only
Identifiers
- Gene
- RAD51C
- Transcript
- NM_058216.3
- Coding (HGVS c.)
- NM_058216.3:c.30G>T
- Protein (HGVS p.)
- NP_478123.1:p.(Met10Ile)
- GRCh38
- chr17:58692673 G>T
- GRCh37
- chr17:56770034 G>T
- ClinVar
- 538784
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
1 / 1,614,238 alleles
AF 6.19e-07 · 0 homozygotes
gnomAD v2.1
1 / 251,450 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,238 alleles · 0 hom
| European (non-Finnish)1 / 1,180,042 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,450 alleles · 0 hom
| European (non-Finnish)1 / 113,738 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19487e-07; MAF= 0.00006%, 1/1614238 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47427e-07; MAF= 0.00008%, 1/1180042 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97693e-06; MAF= 0.00040%, 1/251450 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79214e-06; MAF= 0.00088%, 1/113738 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.240
- BayesDel
- -0.112
How the predictions were used
BP4 SupportingMultiple in silico predictors suggest a benign effect. BayesDel score is -0.112 (negative, consistent with benign), REVEL score is 0.24 (below pathogenic threshold of 0.5), and SpliceAI max delta is 0.04 (no splicing impact). Three independent computational tools converge on a non-damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL=0.24 (below pathogenic threshold)
- BayesDel=-0.112 (benign direction)
- SpliceAI max delta=0.04 (no splice impact)
Sources
PP3 In silico predictors do not support a damaging effect. REVEL score is 0.24 (below typical pathogenic threshold of 0.5), BayesDel score is -0.112 (negative, suggesting benign), and SpliceAI max delta is 0.04 (no predicted splicing impact). Multiple lines of computational evidence do not support pathogenicity. Details ▾Hide ▴
BP7 N/ANM_058216.3:c.30G>T is a missense variant (p.Met10Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.24. BayesDel score = -0.112409.
7 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
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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. It provides the general classification framework and combination rules but does not discuss the RAD51C c.30G>T variant.Does not name this variant
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PMID 34326862 ↗Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.Bhai P et al. · 2021Analysis of sequence and copy number variants in a Canadian patient cohort with familial cancer syndromes. RAD51C pathogenic variants were identified in the cohort at a frequency of 0.4-1.5% across different cancer types, but NM_058216.3:c.30G>T was not specifically reported.Does not name this variant
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PMID 34923718 ↗A decade of RAD51C and RAD51D germline variants in cancer.Boni J et al. · 2022A review of a decade of RAD51C and RAD51D germline variants in cancer. Discusses the spectrum of pathogenic variants in these genes but does not specifically mention NM_058216.3:c.30G>T (p.Met10Ile).Does not name this variant
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PMID 37253112 ↗Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.Hu C et al. · 2023Comprehensive functional characterization of 173 RAD51C missense variants by HDR assay, drug sensitivity, complex formation, and case-control association. p.Met10Ile was not among the 173 variants tested. The study identified 30 deleterious variants in a hotspot at residues 125-168 (Walker A P-loop).Does not name this variant
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PMID 20301575 ↗Fanconi Anemia.Adam MP et al. · 1993GeneReviews entry for Fanconi Anemia. Provides overview of FA genetics including RAD51C (FANCO) but does not discuss NM_058216.3:c.30G>T.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. Provides clinical guidance but does not discuss specific RAD51C variants.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Provides refined classification rules but does not discuss the RAD51C c.30G>T variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,238 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
3 Uncertain significance
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/538784/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-56770034-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-58692673-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-58692673-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_058216.3%3Ac.30G%…
- OncoKB ↗www.oncokb.org/gene/RAD51C/M10I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RAD51C+c.30G%3ET
- 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= 6.19487e-07; MAF= 0.00006%, 1/1614238 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47427e-07; MAF= 0.00008%, 1/1180042 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97693e-06; MAF= 0.00040%, 1/251450 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79214e-06; MAF= 0.00088%, 1/113738 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 538784)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.24. BayesDel score = -0.112409.
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.