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RAD51Dc.641C>TUncertain significance
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Variant interpretation report

RAD51D c.641C>T, p.(Pro214Leu)

NM_002878.3:c.641C>T NP_002869.3:p.(Pro214Leu) 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 RAD51D

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 Not recorded. 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 absent from gnomAD v2.1 and gnomAD-Canada, and present at an extremely low allele frequency in gnomAD v4.1 (AF=0.000124%, 2/1,614,084 alleles, 0 homozygotes). Well below the 0.1% PM2 threshold for dominant disorders.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.266 (below the 0.5 damaging threshold), BayesDel score is 0.181 (below common 0.2–0.3 damaging thresholds), and SpliceAI max delta is 0.00 (no predicted splice impact).

Recorded classification: Uncertain significance

gene-specific framework 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.

SpliceAI score
0.000 maximum delta

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

Applied · BP4 → SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions

5 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. RAD51D, a DNA repair protein, is infrequently altered in cancer.

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 Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 2 met · 9 not met · 12 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=0.000124%, 2/1,614,084 alleles, 0 homozygotes), meeting PM2 at supporting strength.

Multiple in silico tools predict no damaging effect: REVEL score 0.266, BayesDel score 0.181, and SpliceAI max delta 0.00, meeting BP4 at supporting benign strength.

The variant has been reported in ClinVar as Uncertain significance by five clinical laboratories (Variation ID: 574602). No expert panel review or pathogenic/benign classification has been rendered.

No variant-specific functional studies, cosegregation data, de novo observations, or case-control enrichment data are available. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence.

The opposing PM2 (supporting) and BP4 (supporting benign) criteria effectively cancel each other, yielding an evidence framework consistent with Uncertain significance.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at an extremely low allele frequency in gnomAD v4.1 (AF=0.000124%, 2/1,614,084 alleles, 0 homozygotes). Well below the 0.1% PM2 threshold for dominant disorders. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: 2/1
  • 614
  • 084 alleles (AF=1.24e-06
  • grpmax FAF=2.8e-07)
  • gnomAD-Canada v1.0: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.266 (below the 0.5 damaging threshold), BayesDel score is 0.181 (below common 0.2–0.3 damaging thresholds), and SpliceAI max delta is 0.00 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.266 (benign-leaning)
  • BayesDel: 0.181 (benign-leaning)
  • SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
revelbayesdelspliceai ↗

Not met · 9 · evaluated, threshold not reached

PS3 No variant-specific functional studies were identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence for this variant. No publication with functional experimental data for NM_002878.3:c.641C>T was found. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional evidence available.
Still missing
  • No functional assay data (e.g.
  • HR repair
  • RAD51 foci formation) for this variant.
Sources
oncokb ↗
PM1 This variant does not lie in a statistically significant mutational hotspot per CancerHotspots.org, and no domain-level constraint or functional domain data specific to RAD51D missense constraint is available to support PM1 application. Details ▾Hide ▴
Evidence considered
  • CancerHotspots: residue not significant
  • exact variant not listed.
Still missing
  • No RAD51D-specific missense constraint or functional domain tolerance data available for this residue.
PP3 Multiple in silico tools do not support a deleterious effect. REVEL score is 0.266 (below the 0.5 damaging threshold). BayesDel score is 0.181 (below common 0.2–0.3 damaging thresholds). SpliceAI max delta is 0.00 (no splice impact). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.266 (benign-leaning)
  • BayesDel: 0.181 (benign-leaning)
  • SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
revelbayesdelspliceai ↗
PP5 No reputable source has reported this variant as pathogenic. All five ClinVar submitters classify it as Uncertain significance. No expert panel classification exists. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 574602: Uncertain significance from all submitters
  • no expert panel review.
Sources
clinvar ↗
BA1 The maximum allele frequency (gnomAD v4.1 NFE: 0.00017%) is well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Max AF: 1.69e-06 in NFE subpopulation (0.00017%)
  • well below 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 The maximum allele frequency (gnomAD v4.1 NFE: 0.00017%) is well below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Max AF: 1.69e-06 in NFE subpopulation (0.00017%)
  • well below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BS3 No well-established functional studies demonstrating no damaging effect on protein function or splicing are available. OncoKB reports no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional studies showing benign effect.
Still missing
  • No functional assay data demonstrating normal protein function.
Sources
oncokb ↗
BP6 No reputable source has reported this variant as benign. ClinVar classification is Uncertain significance; no benign classification exists from any clinical laboratory. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 574602: Uncertain significance
  • no benign classification from any submitter.
Sources
clinvar ↗
PS5 No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance from all 5 clinical laboratories; no expert panel review has been performed. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 574602: Uncertain significance (5/5 submitters)
  • no expert panel classification.
Sources
clinvar ↗

Not assessed · 12 · no assessment recorded

PS1 No data available to determine whether a different nucleotide change at the same amino acid residue (Pro214) has been established as pathogenic. Details ▾Hide ▴
Still missing
  • No same-residue pathogenic comparator identified in ClinVar or literature.
PS2 No de novo observation with confirmed maternity and paternity is available for this variant. Details ▾Hide ▴
Still missing
  • No de novo data in ClinVar submissions or literature.
PS4 No case-control or cohort data comparing variant prevalence in affected individuals versus controls is available. The ClinVar submissions do not include case counts or odds ratios. Details ▾Hide ▴
Still missing
  • No case-control enrichment data
  • no odds ratio or statistical comparison available.
PM6 No de novo observation (maternity/paternity unconfirmed) has been reported for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports in ClinVar or literature.
PP1 No cosegregation data with disease in families is available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP2 No HCI prior or other gene-level constraint metric is available for RAD51D (gene_not_supported in HCI prior lookup). Cannot assess whether RAD51D has a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
  • HCI prior: gene_not_supported for RAD51D.
Still missing
  • No gene-level missense constraint metric available for RAD51D.
PP4 No detailed clinical phenotype or family history data are available for the probands carrying this variant. ClinVar submissions lack specific phenotype descriptions. Details ▾Hide ▴
Still missing
  • No patient phenotype data available for specificity assessment.
BS2 No data on observation in healthy adult controls for a fully penetrant early-onset disorder. The 2 gnomAD alleles lack phenotype data to confirm healthy status or exclude late-onset disease. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 2 alleles but no phenotype data to confirm healthy status.
Still missing
  • No phenotype data for gnomAD carriers
  • RAD51D-associated cancer risk is moderate-penetrance and often adult-onset.
BS4 No segregation data demonstrating absence of cosegregation with disease is available. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP1 RAD51D loss of function is an established disease mechanism, but missense variants can also be pathogenic via dominant-negative or hypomorphic effects. Without gene-specific data on the proportion of pathogenic variants that are truncating versus missense, BP1 cannot be reliably applied. Details ▾Hide ▴
Evidence considered
  • RAD51D LoF mechanism supported per PVS1 gene context
  • missense pathogenicity not ruled out.
Still missing
  • No gene-specific data on missense vs truncating pathogenic variant ratio for RAD51D.
BP2 No data on observation in trans with a known pathogenic variant in RAD51D. Details ▾Hide ▴
Still missing
  • No trans-observation data available.
BP5 No data on observation of this variant in cases with an alternative molecular basis for disease. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnosis in carriers.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.641C>T, p.Pro214Leu), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The ClinGen SVI PVS1 decision tree does not apply to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Missense substitution classified as variant_bucket='other' by PVS1 scaffold
  • not eligible for generic PVS1 framework.
Sources
pvs1_variant_assessment
PM5 N/ANo established pathogenic missense variant at the same residue (Pro214) with a different amino acid change is available. PM5 candidate harvesting returned no comparators. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found no same-residue pathogenic comparator.
Sources
pm5_candidates
BP3 N/AThis variant is a missense substitution, not an in-frame indel in a non-repeat region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.641C>T, p.Pro214Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
RAD51D
Transcript
NM_002878.3
Coding (HGVS c.)
NM_002878.3:c.641C>T
Protein (HGVS p.)
NP_002869.3:p.(Pro214Leu)
GRCh38
chr17:35103480 G>A
GRCh37
chr17:33430499 G>A
ClinVar
574602

Gene diagram

Every interpreted variant in RAD51D, mapped onto the exon structure of NM_002878.3. Select a row to find it on the plot.

RAD51DNM_002878.3
Fetching transcript structure from UCSC…
gnomAD v4.1 2 / 1,614,084 alleles AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.2e-06 · 2 / 1,614,084 alleles · 0 hom · FAF 2.8e-07
European (non-Finnish)2 / 1,180,012 1.7e-06
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.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.23909e-06; MAF= 0.00012%, 2/1614084 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.6949e-06; MAF= 0.00017%, 2/1180012 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.266
BayesDel
0.181

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.266 (below the 0.5 damaging threshold), BayesDel score is 0.181 (below common 0.2–0.3 damaging thresholds), and SpliceAI max delta is 0.00 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.266 (benign-leaning)
  • BayesDel: 0.181 (benign-leaning)
  • SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico tools do not support a deleterious effect. REVEL score is 0.266 (below the 0.5 damaging threshold). BayesDel score is 0.181 (below common 0.2–0.3 damaging thresholds). SpliceAI max delta is 0.00 (no splice impact). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.266 (benign-leaning)
  • BayesDel: 0.181 (benign-leaning)
  • SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.641C>T, p.Pro214Leu), not a synonymous variant. BP7 applies only to synonymous variants 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 = 0.00). REVEL score = 0.266. BayesDel score = 0.181497.

2 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

  • 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. · 2015
    ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a methodological framework paper; no specific variant data are reported.
    Does not name this variant
    PMID 25741868 ↗
  • 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. · 2015
    ACMG/NSGC practice guideline for referral indications for cancer predisposition assessment. A clinical practice guideline with no variant-specific data.
    Does not name this variant
    PMID 25394175 ↗

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

gnomAD v4.1 2 / 1,614,084 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 5 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 ↗

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= 1.23909e-06; MAF= 0.00012%, 2/1614084 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.6949e-06; MAF= 0.00017%, 2/1180012 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 574602)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.266. BayesDel score = 0.181497.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RAD51D, a DNA repair protein, is infrequently altered in cancer.

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.