0%
RAD51Dc.446T>AUncertain significance
Print report
Variant interpretation report

RAD51D c.446T>A, p.(Leu149Gln)

NM_002878.4:c.446T>A NP_002869.3:p.(Leu149Gln) 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: 0 Benign evidence criteria: 0
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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: none; combination = no applied criteria, 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
0.030 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
1 reported laboratory submissions

1 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.

26 criteria with recorded statuses: 0 met · 7 not met · 17 not assessed · 2 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

NM_002878.4:c.446T>A (p.Leu149Gln) is a missense variant in exon 5 of RAD51D, a moderate-penetrance breast and ovarian cancer susceptibility gene.

Population frequency data from gnomAD v2.1 and v4.1 are unavailable; gnomAD-Canada reports zero observations. The variant cannot be confirmed as absent or rare in population controls.

In silico predictions are inconclusive: REVEL (0.434) is intermediate, BayesDel (0.295) is borderline, and SpliceAI predicts no splicing impact (max delta 0.03). Neither PP3 nor BP4 criteria are met.

The variant is reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics/Invitae, SCV007364796) with criteria provided.

No functional studies, de novo reports, segregation data, case-control studies, or same-residue pathogenic comparators were identified for this variant.

No pathogenic or benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.

Not met · 7 · evaluated, threshold not reached

PS1 No pathogenic or likely pathogenic variant with the same amino acid change (p.Leu149Gln) has been identified in ClinVar or the literature. The ClinVar entry for this exact variant is classified as Uncertain significance. Details ▾Hide ▴
Evidence considered
  • ClinVar variation ID 4705017 is classified as VUS
  • not pathogenic.
Still missing
  • No same-amino-acid pathogenic comparator identified.
Sources
clinvar ↗
PM5 No pathogenic or likely pathogenic missense variant at the same amino acid residue (Leu149) was identified in ClinVar. The automated PM5 candidate search yielded zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue pathogenic/likely pathogenic comparators identified at RAD51D codon 149.
Sources
clinvar ↗
PP3 In silico predictions do not provide consistent evidence of a deleterious effect. REVEL score (0.434) is intermediate, below the typical pathogenic threshold of 0.75. BayesDel score (0.295) is borderline, only marginally above the ~0.27 damaging cutoff. SpliceAI predicts no splicing impact (max delta score 0.03). Multiple lines of computational evidence do not converge on a deleterious prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.434 (intermediate)
  • BayesDel: 0.295 (borderline)
  • SpliceAI max delta: 0.03 (no splice impact).
Still missing
  • No conservation-based scores (GERP
  • PhyloP) or protein structure predictions reviewed.
Sources
revelbayesdelspliceai ↗
PP5 No reputable source reports this variant as pathogenic. The sole ClinVar submission classifies the variant as Uncertain significance. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance (1 submitter
  • criteria provided).
Sources
clinvar ↗
BP4 In silico predictions do not provide consistent evidence of no impact. REVEL score (0.434) is not in the benign range (≤0.15). BayesDel score (0.295) is not clearly below the benign threshold. While SpliceAI predicts no splicing impact (max delta 0.03), multiple lines of computational evidence do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.434 (not benign)
  • BayesDel: 0.295 (borderline
  • not clearly benign)
  • SpliceAI max delta: 0.03 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP6 No reputable source reports this variant as benign. The sole ClinVar submission classifies the variant as Uncertain significance, not benign or likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance (1 submitter)
  • no benign assertion available.
Sources
clinvar ↗
PS5 No reputable source reports this variant as pathogenic. The sole ClinVar submission (Labcorp Genetics/Invitae, SCV007364796) classifies this variant as Uncertain significance, not pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is Uncertain significance from a single clinical laboratory.
Sources
clinvar ↗

Not assessed · 17 · no assessment recorded

PS2 No de novo data are available for this variant. The exploratory literature search yielded no de novo reports. Details ▾Hide ▴
Still missing
  • No de novo testing data or parent-of-origin studies available.
PS3 No well-established functional studies were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional studies found.
Still missing
  • No functional assay data (e.g.
  • homology repair
  • protein interaction
  • cellular viability) for p.Leu149Gln in RAD51D.
Sources
oncokb ↗
PS4 No case-control or cohort studies reporting prevalence of this variant in affected versus control populations were identified. The single ClinVar-associated PMID (28492532) is a methodology paper describing the Sherloc classification framework and does not report variant-specific case observations. Details ▾Hide ▴
Evidence considered
  • PMID:28492532 is a variant classification methodology paper
  • it does not contain case-level prevalence data for this variant.
Still missing
  • No case-control or cohort data comparing prevalence of NM_002878.4:c.446T>A in breast/ovarian cancer patients versus controls.
Sources
PMID:28492532 ↗28492532
PM1 This variant is not located in a statistically significant mutational hotspot. Domain-level assessment of whether codon 149 lies within a critical functional domain without benign variation is not available from the evidence collected. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots analysis: residue not significant. No domain-level constraint or functional domain data available for RAD51D codon 149.
Still missing
  • No RAD51D domain architecture or functional domain data reviewed
  • unable to determine if Leu149 resides in a critical domain without benign variation.
PM2 Population allele frequency data from gnomAD v2.1 and v4.1 are unavailable (null) for this variant; gnomAD-Canada reports zero allele counts with zero total alleles. The absence of coverage data in the major gnomAD datasets precludes confident determination that the variant is truly absent from population controls. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF null
  • gnomAD v4.1: AF null
  • gnomAD-Canada: 0/0 alleles (absent with zeroed source data).
Still missing
  • gnomAD v2.1 and v4.1 population allele frequency data not retrieved
  • unable to assess true population frequency.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM6 No de novo reports for this variant were identified. The exploratory literature search yielded no results. Details ▾Hide ▴
Still missing
  • No de novo testing data available for this variant.
PP1 No cosegregation data are available for this variant. No family studies or linkage analysis were identified in the literature. Details ▾Hide ▴
Still missing
  • No family studies or cosegregation analysis available.
PP2 RAD51D HCI prior data are unavailable. Without gene-level missense constraint metrics (z-score, gnomAD missense constraint), the rate of benign missense variation in RAD51D cannot be evaluated for PP2 applicability. Details ▾Hide ▴
Evidence considered
  • HCI prior not found for RAD51D. No gene-level missense constraint data available.
Still missing
  • No RAD51D missense constraint data or benign missense rate statistics available.
PP4 No patient phenotype or family history data are available for review. PP4 requires a phenotype highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
  • No phenotype or family history information available.
BA1 Population allele frequency data from gnomAD v2.1 and v4.1 are unavailable. The >1% threshold cannot be evaluated without population frequency data. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 and v4.1 allele frequency data not retrieved.
Still missing
  • No population allele frequency data available to evaluate BA1 (>1%).
BS1 Population allele frequency data from gnomAD v2.1 and v4.1 are unavailable. The >0.3% threshold cannot be evaluated without population frequency data. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 and v4.1 allele frequency data not retrieved.
Still missing
  • No population allele frequency data available to evaluate BS1 (>0.3%).
BS2 No homozygous or hemizygous observations of this variant have been reported. gnomAD homozygote data are unavailable. Details ▾Hide ▴
Still missing
  • No data on homozygous or hemizygous observations in healthy adults.
BS3 No well-established functional studies showing no damaging effect were identified for this variant. Details ▾Hide ▴
Still missing
  • No functional assay data available to demonstrate absence of a damaging effect.
BS4 No segregation data are available to evaluate lack of segregation with disease in affected families. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP1 RAD51D is a DNA repair gene where both truncating and missense variants can be pathogenic. RAD51D missense variants have been reported in association with hereditary breast and ovarian cancer. Insufficient evidence to determine that RAD51D is a gene for which primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
  • RAD51D is a moderate-penetrance breast/ovarian cancer susceptibility gene
  • missense variants can be pathogenic.
Still missing
  • No systematic assessment of RAD51D missense versus truncating variant pathogenicity rates reviewed.
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant in RAD51D or other genes. Details ▾Hide ▴
Still missing
  • No trans-configuration data available.
BP5 No data are available regarding an alternate molecular basis for disease in cases harboring this variant. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnoses in carriers of this variant.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Leu149Gln) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • variant_bucket 'other'
  • apply_generic_pvs1_framework is false.
Sources
pvs1_generic_framework ↗
BP7 N/AThis is a missense variant (c.446T>A, p.Leu149Gln), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 is restricted to synonymous variants.

Identifiers

Gene
RAD51D
Transcript
NM_002878.4
Coding (HGVS c.)
NM_002878.4:c.446T>A
Protein (HGVS p.)
NP_002869.3:p.(Leu149Gln)
GRCh38
chr17:35107022 A>T
GRCh37
chr17:33434041 A>T
ClinVar
4705017

Gene diagram

Every interpreted variant in RAD51D, mapped onto the exon structure of NM_002878.4. Select a row to find it on the plot.

RAD51DNM_002878.4
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 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

No population statements were recorded.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +39 bp
0.030
SpliceAI acceptor gainat -2 bp
0.030
SpliceAI donor lossat -34 bp
0.010
SpliceAI donor gainat -458 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.030

Other predictors

REVEL
0.434
BayesDel
0.295

How the predictions were used

PP3 In silico predictions do not provide consistent evidence of a deleterious effect. REVEL score (0.434) is intermediate, below the typical pathogenic threshold of 0.75. BayesDel score (0.295) is borderline, only marginally above the ~0.27 damaging cutoff. SpliceAI predicts no splicing impact (max delta score 0.03). Multiple lines of computational evidence do not converge on a deleterious prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.434 (intermediate)
  • BayesDel: 0.295 (borderline)
  • SpliceAI max delta: 0.03 (no splice impact).
Still missing
  • No conservation-based scores (GERP
  • PhyloP) or protein structure predictions reviewed.
Sources
revelbayesdelspliceai ↗
BP4 In silico predictions do not provide consistent evidence of no impact. REVEL score (0.434) is not in the benign range (≤0.15). BayesDel score (0.295) is not clearly below the benign threshold. While SpliceAI predicts no splicing impact (max delta 0.03), multiple lines of computational evidence do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.434 (not benign)
  • BayesDel: 0.295 (borderline
  • not clearly benign)
  • SpliceAI max delta: 0.03 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.446T>A, p.Leu149Gln), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 is restricted to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.434. BayesDel score = 0.294753.

1 paper record 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

  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Describes the Sherloc refinement of ACMG-AMP variant classification criteria through iterative classification of over 40,000 clinically observed variants. NM_002878.4:c.446T>A (p.Leu149Gln) was not identified in this paper.
    Does not name this variant
    PMID 28492532 ↗

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

SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗
ClinVar 1 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.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4705017)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.434. BayesDel score = 0.294753.

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.