0%
RAD51Cc.848C>TUncertain significance
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Variant interpretation report

RAD51C c.848C>T, p.(Thr283Ile)

NM_058216.3:c.848C>T NP_478123.1:p.(Thr283Ile) 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

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 criterion for absence from population databases under generic ACMG/AMP 2015 guidelines.

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.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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
COSMIC ↗Cancer Hotspots ↗
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: 1 met · 22 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The variant NM_058216.3:c.848C>T (p.Thr283Ile) in RAD51C is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting PM2 at supporting strength.

The variant is a missense change not triggering PVS1. No alternative pathogenic missense at the same residue (PM5), no de novo observations (PS2/PM6), no functional studies (PS3/BS3), no case-control or prevalence data (PS4), no segregation data (PP1/BS4), and no patient phenotype data (PP4) are available.

In silico predictors are mixed: REVEL (0.308) is indeterminate, BayesDel (0.074) is in the benign range, and SpliceAI predicts no splice impact (0.00). Neither PP3 nor BP4 is met.

The RAD51C Hereditary Breast, Ovarian and Pancreatic Cancer VCEP specification (v1.0.0, doc_id 1535377178) is in preparation and does not provide finalized criterion-specific rules. Assessment defaults to generic ACMG/AMP 2015 guidelines (PMID:25741868).

Under generic ACMG/AMP 2015 combination rules, a single supporting pathogenic criterion (PM2) is insufficient to reach Likely Pathogenic. No benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 1

PM2 SupportingThe variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 criterion for absence from population databases under generic ACMG/AMP 2015 guidelines. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • absent from gnomAD v4.1 (exomes)
  • absent from gnomAD-Canada v1.0 (genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 22 · evaluated, threshold not reached

PS1 No alternative nucleotide change at codon 848 producing the same p.Thr283Ile amino acid substitution has been reported as pathogenic. The variant is absent from ClinVar, and no pathogenic comparator at this residue exists in available databases. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic same-amino-acid comparators identified.
Still missing
  • No ClinVar entries exist for this residue
  • a novel pathogenic same-codon substitution could emerge in future submissions.
Sources
clinvar ↗
PS2 No de novo observation with confirmed maternity and paternity has been reported for this variant in any available source. Details ▾Hide ▴
Evidence considered
  • No de novo data available from any evidence source.
Still missing
  • No family studies or parent-of-origin testing data available.
PS3 No well-established in vitro or in vivo functional studies assessing the impact of p.Thr283Ile on RAD51C protein function were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB reports no variant-specific reviewed functional evidence.
Still missing
  • No functional assay data available
  • experimental characterization of RAD51C p.Thr283Ile would be required to assess PS3.
Sources
oncokb ↗
PS4 No case-control studies or prevalence comparisons between affected individuals and controls are available. The variant has not been reported in any affected individual in ClinVar, COSMIC, or the literature. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • absent from COSMIC
  • no case reports identified.
Still missing
  • No affected individuals reported
  • case-control data unavailable.
Sources
clinvar ↗
PM1 The p.Thr283Ile substitution does not lie within a statistically significant mutational hotspot in RAD51C, and no VCEP-defined critical functional domain assignment is available for this residue. Details ▾Hide ▴
Evidence considered
  • Residue 283 is not in a statistically significant hotspot
  • no domain-level functional annotation assigns this as a critical residue.
Still missing
  • Domain-level functional annotation of RAD51C residue Thr283 is not available from the CSPEC/VCEP.
PM5 No pathogenic missense variant at the same amino acid residue (Thr283) with a different amino acid change has been identified. The PM5 candidate search returned no comparator variants at this residue. Details ▾Hide ▴
Evidence considered
  • Automated PM5 candidate search found no same-residue pathogenic comparators
  • ClinVar has no entries at this position.
Still missing
  • No same-residue pathogenic comparators exist in available databases.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (with or without confirmed maternity and paternity) has been reported for this variant. PM6 requires at least a de novo observation without parental confirmation. Details ▾Hide ▴
Evidence considered
  • No de novo data available from any evidence source.
Still missing
  • No de novo testing or family studies available.
PP1 No cosegregation data are available. No family studies or pedigrees including this variant have been reported. Details ▾Hide ▴
Evidence considered
  • No family or cosegregation data available.
Still missing
  • No pedigree or segregation analysis data.
PP2 RAD51C is not included in the HCI prior gene set, so a gene-level missense constraint metric cannot be calculated. Without evidence that RAD51C has a low rate of benign missense variation and that missense variants are a common pathogenic mechanism, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
  • HCI prior data not available for RAD51C
  • gene not in supported set.
Still missing
  • No gene-level missense constraint metric available for RAD51C.
PP3 In silico predictors do not support a deleterious effect. REVEL score is 0.308 (below the 0.5 threshold for pathogenicity), BayesDel score is 0.074 (within the benign range), and SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL score 0.308 (indeterminate
  • not in pathogenic range)
  • BayesDel score 0.074 (benign-leaning)
  • SpliceAI max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for RAD51C-associated disease (hereditary breast/ovarian cancer, Fanconi anemia). Details ▾Hide ▴
Evidence considered
  • No patient phenotype or family history data available.
Still missing
  • No clinical phenotype data for the individual carrying this variant.
PP5 No reputable source (clinical laboratory, curated database, or expert panel) has reported this variant as pathogenic with unavailable supporting evidence. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no laboratory or expert panel classification exists.
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, far below the BA1 threshold of >1% (or >0.1% for recessive Fanconi anemia context). Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0% in all gnomAD datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from population databases. The observed allele frequency (0%) is not greater than expected for the disorder; BS1 requires an allele frequency higher than expected for the disease prevalence. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0% in all gnomAD datasets
  • not elevated relative to disease prevalence.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 The variant has not been observed in any individual (healthy or affected) in available databases. No healthy adult observation data exist to apply BS2. Details ▾Hide ▴
Evidence considered
  • No observation in any individual.
Still missing
  • No healthy adult carrier data available.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect of this variant on RAD51C protein function or splicing are available. Details ▾Hide ▴
Evidence considered
  • No functional studies available for this variant.
Still missing
  • No functional characterization of p.Thr283Ile has been performed.
BS4 No segregation data are available to assess lack of cosegregation with disease. BS4 requires evidence that the variant does not segregate with disease in affected family members. Details ▾Hide ▴
Evidence considered
  • No family or segregation data available.
Still missing
  • No pedigree or segregation analysis data.
BP2 No observation of this variant in trans with a known pathogenic RAD51C variant has been reported for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
  • No trans-phase observation data available.
Still missing
  • No phase data from family studies or sequencing.
BP4 Computational predictors yield mixed results: BayesDel (0.074) is in the benign range and SpliceAI (0.00) predicts no splice impact, but REVEL (0.308) is indeterminate and does not clearly support a benign effect. Multiple lines of evidence do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
  • REVEL 0.308 (indeterminate)
  • BayesDel 0.074 (benign range)
  • SpliceAI 0.00 (no splice impact). Mixed signals
  • no consensus benign prediction.
Sources
revelbayesdelspliceai ↗
BP5 No case has been reported in which this variant is found in an individual with an alternate molecular basis for disease. No case-level data are available. Details ▾Hide ▴
Evidence considered
  • No case data or alternate molecular basis evidence available.
Still missing
  • No patient-level data available.
BP6 No reputable source (clinical laboratory, curated database, or expert panel) has reported this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification exists from any source.
Sources
clinvar ↗
PS5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. No case-level data are available. Details ▾Hide ▴
Evidence considered
  • No case data or alternate molecular basis evidence available.
Still missing
  • No patient-level data available.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_058216.3:c.848C>T is a missense variant (p.Thr283Ile) and does not fall into the null-variant buckets of nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or exon-level deletion that trigger PVS1 under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant in exon 5
  • variant bucket classified as 'other'
  • no canonical splice site involvement.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
BP1 N/ARAD51C is known to harbor pathogenic missense variants (e.g., homozygous missense reported in Fanconi anemia-like disorder, PMID:20400963). BP1 is only applicable to genes where truncating variants are the sole disease mechanism. Details ▾Hide ▴
Evidence considered
  • Pathogenic missense variants documented in RAD51C in both autosomal dominant (breast/ovarian cancer) and autosomal recessive (Fanconi anemia) contexts.
Sources
pvs1_gene_context
BP7 N/ANM_058216.3:c.848C>T is a missense variant (p.Thr283Ile), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 criterion restricted to synonymous variants.

Identifiers

Gene
RAD51C
Transcript
NM_058216.3
Coding (HGVS c.)
NM_058216.3:c.848C>T
Protein (HGVS p.)
NP_478123.1:p.(Thr283Ile)
GRCh38
chr17:58720756 C>T
GRCh37
chr17:56798117 C>T

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 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.000

Other predictors

REVEL
0.308
BayesDel
0.074

How the predictions were used

PP3 In silico predictors do not support a deleterious effect. REVEL score is 0.308 (below the 0.5 threshold for pathogenicity), BayesDel score is 0.074 (within the benign range), and SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL score 0.308 (indeterminate
  • not in pathogenic range)
  • BayesDel score 0.074 (benign-leaning)
  • SpliceAI max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP4 Computational predictors yield mixed results: BayesDel (0.074) is in the benign range and SpliceAI (0.00) predicts no splice impact, but REVEL (0.308) is indeterminate and does not clearly support a benign effect. Multiple lines of evidence do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
  • REVEL 0.308 (indeterminate)
  • BayesDel 0.074 (benign range)
  • SpliceAI 0.00 (no splice impact). Mixed signals
  • no consensus benign prediction.
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_058216.3:c.848C>T is a missense variant (p.Thr283Ile), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 criterion restricted to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.308. BayesDel score = 0.0741864.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.308. BayesDel score = 0.0741864.

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.