0%
RAD51Dc.198G>TLikely benign
Print report
Variant interpretation report

RAD51D c.198G>T, p.(Val66=)

NM_002878.4:c.198G>T NP_002869.3:p.(Val66=) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

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: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BS1Supporting
BS1 · supporting

The gnomAD v4.1 grpmax filtering allele frequency is 0.303%, marginally exceeding the 0.3% threshold for BS1. In the East Asian subpopulation, the allele frequency is 0.348% (156/44,880 alleles) with one homozygote observed, indicating the variant is too common in the general population to be a highly penetrant pathogenic variant for RAD51D-associated autosomal dominant cancer predisposition. The borderline frequency and the v2.1 grpmax FAF of 0.022% (below threshold) warrant supporting rather than strong strength.

BP6Supporting
BP6 · supporting

Multiple reputable clinical diagnostic laboratories have classified NM_002878.4:c.198G>T as Likely benign (Labcorp/Invitae, Color Health, GeneDx, Ambry Genetics, Counsyl) or Benign (Myriad Genetics) in ClinVar (Variation ID: 184496). The underlying evidence criteria are not publicly available for independent evaluation, so BP6 is applied at supporting strength.

BP7Supporting
BP7 · supporting

NM_002878.4:c.198G>T is a synonymous variant (p.Val66=) with no predicted amino acid change. SpliceAI predicts no splice impact (max delta score = 0.00), and no novel splice site creation is predicted. This meets the ACMG/AMP BP7 criterion for synonymous variants without predicted splicing consequences.

Recorded classification: Likely benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 supporting, BP6 supporting, BP7 supporting; combination = 3 supporting benign, which maps to Likely Benign.

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
157 / 1,614,202 alleles

gnomAD v4.1: 157 / 1,614,202 alleles. Recorded AF 9.72617e-05. Recorded homozygote count 1.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.57927e-05; MAF= 0.00358%, 9/251448 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000434972; MAF= 0.04350%, 8/18392 alleles, homozygotes = 0); grpmax FAF= 0.00021573.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · BS1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

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

Applied · BP7 → SpliceAI ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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.

29 criteria with recorded statuses: 3 met · 4 not met · 12 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002878.4:c.198G>T (p.Val66=) is a synonymous variant in RAD51D with no predicted amino acid change.

SpliceAI predicts no splice impact for this variant (max delta score = 0.00), meeting BP7 (supporting).

This variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.303% and an East Asian subpopulation frequency of 0.348% (156/44,880 alleles, one homozygote), marginally exceeding the 0.3% threshold for BS1 at supporting strength.

Multiple clinical diagnostic laboratories have classified this variant as Likely benign (5 labs) or Benign (1 lab) in ClinVar (Variation ID: 184496), consistent with BP6 at supporting strength.

No variant-specific functional, segregation, de novo, or case-control data were identified in the literature. Three PMIDs from ClinVar (25741868, 25394175, 28492532) are guideline or methods papers that do not mention NM_002878.4:c.198G>T.

Met · 3

BS1 SupportingThe gnomAD v4.1 grpmax filtering allele frequency is 0.303%, marginally exceeding the 0.3% threshold for BS1. In the East Asian subpopulation, the allele frequency is 0.348% (156/44,880 alleles) with one homozygote observed, indicating the variant is too common in the general population to be a highly penetrant pathogenic variant for RAD51D-associated autosomal dominant cancer predisposition. The borderline frequency and the v2.1 grpmax FAF of 0.022% (below threshold) warrant supporting rather than strong strength. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 grpmax FAF = 0.303% (>0.3% BS1 threshold)
  • gnomAD v4.1 East Asian AF = 0.348% (156/44
  • 880) with 1 homozygote
  • gnomAD v2.1 grpmax FAF = 0.022% (below threshold
  • v4.1 provides stronger evidence)
Still missing
  • BS1 is borderline (0.303% vs 0.3% threshold)
  • v2.1 grpmax FAF was below threshold
Sources
gnomad_v4 ↗gnomad_v2 ↗
BP6 SupportingMultiple reputable clinical diagnostic laboratories have classified NM_002878.4:c.198G>T as Likely benign (Labcorp/Invitae, Color Health, GeneDx, Ambry Genetics, Counsyl) or Benign (Myriad Genetics) in ClinVar (Variation ID: 184496). The underlying evidence criteria are not publicly available for independent evaluation, so BP6 is applied at supporting strength. Details ▾Hide ▴
Evidence considered
  • ClinVar Likely benign: Labcorp/Invitae (SCV000561575)
  • Color Health (SCV000537457)
  • GeneDx (SCV000514355)
  • Ambry Genetics (SCV000214339)
  • Counsyl (SCV000488844)
  • LabCorp (SCV001338661)
  • ClinVar Benign: Myriad Genetics (SCV004017718)
Still missing
  • Individual laboratory evidence is not publicly accessible for independent verification
Sources
clinvar ↗
BP7 SupportingNM_002878.4:c.198G>T is a synonymous variant (p.Val66=) with no predicted amino acid change. SpliceAI predicts no splice impact (max delta score = 0.00), and no novel splice site creation is predicted. This meets the ACMG/AMP BP7 criterion for synonymous variants without predicted splicing consequences. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.Val66= (no amino acid change)
  • SpliceAI max delta = 0.00 (no predicted splice impact
  • no novel splice site)
Sources
spliceai ↗

Not met · 4 · evaluated, threshold not reached

PS4 The variant is present in gnomAD at low frequency (v2.1: 0.004%, v4.1: 0.010%) with one homozygote in v4.1. No case-control data show enrichment in affected individuals; prevalence in the general population does not support pathogenicity. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF=0.004% (9/251
  • 448)
  • gnomAD v4.1 AF=0.010% (157/1
  • 614
  • 202) with 1 homozygote
Still missing
  • No case-control study of this variant in RAD51D-associated cancer cohorts
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM1 This variant does not lie in a statistically significant mutational hotspot in RAD51D. Details ▾Hide ▴
Evidence considered
  • Variant is not located in a statistically significant hotspot region
PP5 PP5 requires a reputable source to report the variant as pathogenic. ClinVar classification for this variant is Likely benign (7 clinical laboratories) and Benign (1 clinical laboratory). No reputable source has reported it as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: Likely benign (7 labs)
  • Benign (1 lab)
  • no pathogenic classification from any submitter
Sources
clinvar ↗
BA1 The gnomAD grpmax filtering allele frequency is 0.303% (v4.1), which is well below the 1% BA1 threshold. BA1 requires allele frequency >1% in a population database. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 grpmax FAF = 0.303%
  • below the 1% BA1 threshold
Sources
gnomad_v4 ↗

Not assessed · 12 · no assessment recorded

PS2 No de novo data available for NM_002878.4:c.198G>T. Details ▾Hide ▴
Still missing
  • No de novo data identified in literature or ClinVar submissions
PS3 No well-established functional studies identified for this specific variant. The three PMIDs from ClinVar are guideline/methods papers (25741868, 25394175, 28492532) that do not contain variant-specific functional data. Details ▾Hide ▴
Still missing
  • No variant-specific functional assays identified
PM2 While the overall gnomAD allele frequency is below the 0.1% PM2 threshold (v2.1: 0.004%, v4.1: 0.010%), the gnomAD v4.1 grpmax filtering allele frequency is 0.303%, meeting BS1. BS1 provides stronger population-level evidence in the benign direction and supersedes PM2. PM2 is therefore not assessed independently. Details ▾Hide ▴
Evidence considered
  • Overall AF < 0.1% but grpmax FAF 0.303% triggers BS1
  • BS1 supersedes PM2
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM6 No de novo data available for NM_002878.4:c.198G>T. Details ▾Hide ▴
Still missing
  • No de novo data identified in literature or ClinVar submissions
PP1 No segregation data available for NM_002878.4:c.198G>T. Details ▾Hide ▴
Still missing
  • No family segregation data identified
PP4 No phenotype or disease-specificity data available for NM_002878.4:c.198G>T. Details ▾Hide ▴
Still missing
  • No phenotype specificity or clinical correlation data identified
BS2 While one homozygote is observed in gnomAD v4.1, the individuals in gnomAD are not specifically confirmed as healthy adults. RAD51D has moderate/incomplete penetrance with adult-onset cancer, limiting the applicability of BS2 which requires full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
  • 1 homozygote in gnomAD v4.1
  • gnomAD individuals not explicitly confirmed as healthy adults
Still missing
  • Lack of confirmed healthy adult status for gnomAD homozygote
  • incomplete penetrance of RAD51D
Sources
gnomad_v4 ↗
BS3 No well-established functional studies showing no damaging effect were identified for NM_002878.4:c.198G>T. The synonymous nature and SpliceAI delta of 0.00 are computational, not functional, evidence. Details ▾Hide ▴
Still missing
  • No variant-specific functional assays identified (e.g.
  • splicing assays
  • protein function)
BS4 No segregation data available for NM_002878.4:c.198G>T. Details ▾Hide ▴
Still missing
  • No family segregation data identified
BP2 No data on observation of NM_002878.4:c.198G>T in trans with a known pathogenic RAD51D variant. Details ▾Hide ▴
Still missing
  • No data on co-occurrence in trans with pathogenic variants
BP4 BP4 (multiple lines of computational evidence suggest no impact) is subsumed by BP7 for this synonymous variant. SpliceAI delta = 0.00 supports the absence of splice impact. BP7 provides the more specific assessment. Details ▾Hide ▴
Evidence considered
  • SpliceAI delta = 0.00
  • subsumed by BP7 assessment
Sources
spliceai ↗
PS5 No reputable source has reported NM_002878.4:c.198G>T as pathogenic. ClinVar classification is Likely benign/Benign. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign (7 labs)
  • Benign (1 lab)
Sources
clinvar ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002878.4:c.198G>T is a synonymous variant (p.Val66=) that does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is not applicable to synonymous variants. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Val66=) — no protein truncation or canonical splice disruption
Sources
pvs1_generic_framework ↗
PS1 N/APS1 requires a same amino acid change as a previously established pathogenic variant. This is a synonymous variant (p.Val66=) with no amino acid change; the PS1 concept does not apply to synonymous variants. Details ▾Hide ▴
Evidence considered
  • Synonymous variant — no amino acid change to compare with pathogenic variants
PM3 N/APM3 applies to recessive disorders when the variant is detected in trans with a pathogenic variant. RAD51D is associated with autosomal dominant cancer predisposition; PM3 does not apply. Details ▾Hide ▴
Evidence considered
  • RAD51D is autosomal dominant
  • PM3 applies only to recessive disorders
PM4 N/APM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. NM_002878.4:c.198G>T is a synonymous substitution with no protein length change. Details ▾Hide ▴
Evidence considered
  • Synonymous substitution — no protein length change
PM5 N/APM5 requires a novel missense amino acid change at the same residue as a known pathogenic missense variant. NM_002878.4:c.198G>T is synonymous (p.Val66=) and has no amino acid change; PM5 does not apply. Confirmed by pm5_candidates.json: residue context could not be parsed for a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Synonymous variant — no amino acid change to compare at the same residue
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. NM_002878.4:c.198G>T is a synonymous variant (p.Val66=); PP2 does not apply to synonymous variants. Details ▾Hide ▴
Evidence considered
  • Synonymous variant — PP2 is specific to missense variants
PP3 N/APP3 applies when multiple lines of computational evidence support a deleterious effect. This is a synonymous variant (p.Val66=) with SpliceAI max delta score of 0.00 (no predicted splice impact). REVEL and BayesDel scores are unavailable for synonymous variants. Computational evidence does not support pathogenicity; BP7 is the applicable criterion. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • SpliceAI delta = 0.00
  • REVEL/BayesDel not applicable
Sources
spliceai ↗
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary pathogenic mechanism. NM_002878.4:c.198G>T is a synonymous variant (p.Val66=); BP1 does not apply. Details ▾Hide ▴
Evidence considered
  • Synonymous variant — BP1 is specific to missense variants
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions. NM_002878.4:c.198G>T is a single nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
  • Substitution variant — BP3 applies only to in-frame indels
BP5 N/ABP5 applies when a variant is found in a case with an alternate molecular basis for disease. No alternate molecular basis has been identified, and BP5 is not independently assessed in the absence of such evidence. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis identified

Identifiers

Gene
RAD51D
Transcript
NM_002878.4
Coding (HGVS c.)
NM_002878.4:c.198G>T
Protein (HGVS p.)
NP_002869.3:p.(Val66=)
GRCh38
chr17:35118566 C>A
GRCh37
chr17:33445585 C>A
ClinVar
184496

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 v4.1 157 / 1,614,202 alleles AF 9.73e-05 · 1 homozygotes · FAF 0.00303
gnomAD v2.1 9 / 251,448 alleles AF 3.58e-05 · 0 homozygotes · FAF 0.000216
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 9.7e-05 · 157 / 1,614,202 alleles · 1 hom · FAF 0.003
East Asian156 / 44,880 0.00351 hom
Remaining individuals1 / 62,508 1.6e-05
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

gnomAD v2.1

AF 3.6e-05 · 9 / 251,448 alleles · 0 hom · FAF 0.00022
East Asian8 / 18,392 0.00043
Remaining individuals1 / 6,136 0.00016
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 9.72617e-05; MAF= 0.00973%, 157/1614202 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00347594; MAF= 0.34759%, 156/44880 alleles, homozygotes = 1); grpmax FAF= 0.00303071.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.57927e-05; MAF= 0.00358%, 9/251448 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000434972; MAF= 0.04350%, 8/18392 alleles, homozygotes = 0); grpmax FAF= 0.00021573.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.020

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP7 SupportingNM_002878.4:c.198G>T is a synonymous variant (p.Val66=) with no predicted amino acid change. SpliceAI predicts no splice impact (max delta score = 0.00), and no novel splice site creation is predicted. This meets the ACMG/AMP BP7 criterion for synonymous variants without predicted splicing consequences. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.Val66= (no amino acid change)
  • SpliceAI max delta = 0.00 (no predicted splice impact
  • no novel splice site)
Sources
spliceai ↗
BP4 BP4 (multiple lines of computational evidence suggest no impact) is subsumed by BP7 for this synonymous variant. SpliceAI delta = 0.00 supports the absence of splice impact. BP7 provides the more specific assessment. Details ▾Hide ▴
Evidence considered
  • SpliceAI delta = 0.00
  • subsumed by BP7 assessment
Sources
spliceai ↗
PP3 N/APP3 applies when multiple lines of computational evidence support a deleterious effect. This is a synonymous variant (p.Val66=) with SpliceAI max delta score of 0.00 (no predicted splice impact). REVEL and BayesDel scores are unavailable for synonymous variants. Computational evidence does not support pathogenicity; BP7 is the applicable criterion. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • SpliceAI delta = 0.00
  • REVEL/BayesDel not applicable
Sources
spliceai ↗

Statement

In silico

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

3 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
    This is the ACMG/AMP 2015 standards and guidelines for sequence variant interpretation. It is a consensus methods paper describing the classification framework. NM_002878.4:c.198G>T is not mentioned.
    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. This is a clinical practice guideline and does not discuss specific RAD51D variants. NM_002878.4:c.198G>T is not mentioned.
    Does not name this variant
    PMID 25394175 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methods paper describing the Sherloc classification system. NM_002878.4:c.198G>T is not mentioned.
    Does not name this variant
    PMID 28492532 ↗

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

gnomAD v4.1 157 / 1,614,202 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 7 Likely benign · 1 Benign 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= 9.72617e-05; MAF= 0.00973%, 157/1614202 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00347594; MAF= 0.34759%, 156/44880 alleles, homozygotes = 1); grpmax FAF= 0.00303071.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.57927e-05; MAF= 0.00358%, 9/251448 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000434972; MAF= 0.04350%, 8/18392 alleles, homozygotes = 0); grpmax FAF= 0.00021573.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 184496)

In silico

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

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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.