RAD51Bc.1111C>TUncertain significance

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Variant interpretation report

RAD51B c.1111C>T, p.(Gln371Ter)

NM_133509.4:c.1111C>T NP_598193.2:p.(Gln371Ter) 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 RAD51B

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 27 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (moderate): NM_133509.4:c.1111C>T is a nonsense variant predicting p.(Gln371Ter) in exon 11 (the last coding exon) of RAD51B. Loss of function is an established disease mechanism for RAD51B, supported by germline literature identifying truncating mutations in breast cancer, ovarian cancer, and melanoma families. Under the ClinGen SVI PVS1 framework (PMC6185798), this variant is eligible for PVS1. However, the premature termination codon is in the last exon where nonsense-mediated decay is not predicted, and only 13 C-terminal amino acids (3.4% of the protein) are truncated. Per PMC6185798, nonsense variants in the last exon where NMD is not expected are assigned PVS1 at moderate strength.
PM2 (supporting): This variant is present at an extremely low frequency in population databases. In gnomAD v4.1, it is observed at an allele frequency of 4.53 × 10⁻⁶ (6/1,324,198 alleles, 0 homozygotes), with the highest subpopulation frequency of 5.97 × 10⁻⁶ in the European (non-Finnish) population. The variant is absent from gnomAD v2.1 and gnomAD-Canada. This frequency is well below the 0.1% PM2 threshold for a dominant disorder.

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: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Moderate

PVS1 · moderate

NM_133509.4:c.1111C>T is a nonsense variant predicting p.(Gln371Ter) in exon 11 (the last coding exon) of RAD51B. Loss of function is an established disease mechanism for RAD51B, supported by germline literature identifying truncating mutations in breast cancer, ovarian cancer, and melanoma families. Under the ClinGen SVI PVS1 framework (PMC6185798), this variant is eligible for PVS1. However, the premature termination codon is in the last exon where nonsense-mediated decay is not predicted, and only 13 C-terminal amino acids (3.4% of the protein) are truncated. Per PMC6185798, nonsense variants in the last exon where NMD is not expected are assigned PVS1 at moderate strength.

PM2Supporting

PM2 · supporting

This variant is present at an extremely low frequency in population databases. In gnomAD v4.1, it is observed at an allele frequency of 4.53 × 10⁻⁶ (6/1,324,198 alleles, 0 homozygotes), with the highest subpopulation frequency of 5.97 × 10⁻⁶ in the European (non-Finnish) population. The variant is absent from gnomAD v2.1 and gnomAD-Canada. This frequency is well below the 0.1% PM2 threshold for a dominant disorder.

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: PVS1 moderate, PM2 supporting; combination = 1 moderate + 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.

gnomAD v4.1

gnomAD v2.1

Population frequency

6 / 1,324,198 alleles

gnomAD v4.1: 6 / 1,324,198 alleles. Recorded AF 4.53104e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.090 maximum delta

Recorded SpliceAI maximum delta score: 0.090. 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 identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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: 2 met · 19 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_133509.4:c.1111C>T is a nonsense variant predicting p.(Gln371Ter) in exon 11 of RAD51B. Loss of function is an established germline disease mechanism for RAD51B, supported by reports of truncating mutations in breast cancer, ovarian cancer, and melanoma families.

The premature termination codon is in the last exon where nonsense-mediated decay is not predicted, and only 13 C-terminal amino acids are truncated. Under the ClinGen SVI PVS1 framework (PMC6185798), a nonsense variant in the last exon with established LOF mechanism qualifies for PVS1 at moderate strength.

This variant is present at extremely low frequency in gnomAD v4.1 (AF = 4.53 × 10⁻⁶, 6/1,324,198 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada, satisfying PM2 at supporting strength for a rare disease variant.

The variant is absent from ClinVar and has not been reported in any published case-control study. No variant-specific functional data or segregation data are available. The C-terminal tail (residues 371–384) has not been functionally characterized.

OncoKB classifies this variant as Likely Oncogenic with a predicted loss-of-function mechanism, consistent with the established role of RAD51B in homologous recombination repair. Gene-level functional studies demonstrate that RAD51B haploinsufficiency causes centrosome fragmentation, aneuploidy, and impaired homologous recombination.

Combined evidence: PVS1_Moderate + PM2_Supporting. No benign criteria are met. Using the ACMG/AMP 2015 combination rules, this classification reaches Likely Pathogenic.

Met · 2

PVS1 ModerateNM_133509.4:c.1111C>T is a nonsense variant predicting p.(Gln371Ter) in exon 11 (the last coding exon) of RAD51B. Loss of function is an established disease mechanism for RAD51B, supported by germline literature identifying truncating mutations in breast cancer, ovarian cancer, and melanoma families. Under the ClinGen SVI PVS1 framework (PMC6185798), this variant is eligible for PVS1. However, the premature termination codon is in the last exon where nonsense-mediated decay is not predicted, and only 13 C-terminal amino acids (3.4% of the protein) are truncated. Per PMC6185798, nonsense variants in the last exon where NMD is not expected are assigned PVS1 at moderate strength. Details ▾Hide ▴

Evidence considered

Nonsense variant p.(Gln371Ter) in exon 11 (last exon) — no NMD expected
Loss of function is an established germline disease mechanism for RAD51B
PMID:25600502 reports a germline RAD51B nonsense mutation (c.139C>T
p.Arg47*) causing melanoma predisposition
PMID:24139550 reports first germline RAD51B truncating mutation (c.452+3A>G) in breast/ovarian cancer
Only 13 C-terminal amino acids (371–384) are truncated

Still missing

No functional characterization of the C-terminal tail region (residues 371–384) is available
Confirm transcript NM_133509.4 is the biologically relevant isoform

Sources

pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:25600502 ↗

PM2 SupportingThis variant is present at an extremely low frequency in population databases. In gnomAD v4.1, it is observed at an allele frequency of 4.53 × 10⁻⁶ (6/1,324,198 alleles, 0 homozygotes), with the highest subpopulation frequency of 5.97 × 10⁻⁶ in the European (non-Finnish) population. The variant is absent from gnomAD v2.1 and gnomAD-Canada. This frequency is well below the 0.1% PM2 threshold for a dominant disorder. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: AF = 4.53e-06 (6/1
324
198)
0 homozygotes
gnomAD v2.1: absent
gnomAD-Canada v1.0: absent
AF < 0.1% threshold for PM2 is satisfied
grpmax FAF = 2.15e-06

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 19 · evaluated, threshold not reached

PS1 No prior pathogenic classification exists for the same amino acid change p.(Gln371Ter). PS1 requires a previously classified pathogenic variant at the same residue. The variant is absent from ClinVar entirely. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar — no prior pathogenic classification at codon 371

Sources

clinvar ↗

PS2 No de novo testing data are available for this variant. PS2 requires confirmation of de novo occurrence with both maternity and paternity confirmed. No case-level data were provided. Details ▾Hide ▴

Still missing

No parental testing data available

PS3 No variant-specific functional data exist for NM_133509.4:c.1111C>T (p.Gln371Ter). Five publications were reviewed in full text: PMID:16778173 (haploinsufficiency study using engineered RAD51B knockout in HCT116 cells), PMID:24139550 (first germline RAD51B truncating mutation c.452+3A>G), PMID:25368520 (siRNA knockdown in breast cancer cell lines), PMID:25600502 (germline RAD51B c.139C>T, p.Arg47* in melanoma family), and PMID:26261251 (population screening of RAD51B/C/D in ovarian cancer). None tested or reported the variant c.1111C>T / Q371*. The functional studies provide gene-level support for RAD51B LOF pathogenicity but do not satisfy PS3's requirement for variant-specific experimental data. Details ▾Hide ▴

Evidence considered

None of 5 full-text publications tested NM_133509.4:c.1111C>T or a systematically characterized range including position 371
Gene-level functional studies (RAD51B knockout/knockdown) demonstrate LOF pathogenicity mechanism but do not constitute variant-specific PS3 evidence

Still missing

No variant-specific functional assay is available
The C-terminal tail (residues 371–384) has not been functionally characterized

PS4 Prevalence of this variant in affected individuals versus controls is unknown. The largest RAD51B case-control study (PMID:26261251) screened 3,429 ovarian cancer cases and 2,772 controls, identifying only two RAD51B deleterious mutations (G217X and Q219X), neither of which is this variant. No case-control data exist for NM_133509.4:c.1111C>T specifically. Details ▾Hide ▴

Evidence considered

Not observed among 3
429 ovarian cancer cases screened in RAD51B population study

Still missing

No case-control study has reported this specific variant

Sources

PMID:26261251 ↗

PM1 The variant lies at residue 371 in the extreme C-terminal tail of RAD51B (384 amino acids), truncating only 13 C-terminal residues. This region is not annotated as a critical functional domain. Cancerhotspots.org reports no statistically significant hotspot at this residue. No characterized functional domain (ATP-binding, RAD51C-interaction, or BCDX2 complex formation) is disrupted by this C-terminal truncation. The well-characterized functional domains of RAD51B (RAD51C interaction, ATP-binding) are N-terminal to this position. Details ▾Hide ▴

Evidence considered

Cancerhotspots.org: residue 371 not a statistically significant hotspot
C-terminal 13 residues are not part of the characterized ATP-binding or RAD51C interaction domains
RAD51B functional domains mapped N-terminal to position 371

Still missing

Functional significance of the C-terminal tail (residues 371–384) has not been characterized

Sources

PMID:16778173 ↗PMID:26261251 ↗

PM5 PM5 applies when a different pathogenic missense change has been identified at the same amino acid residue. This variant is a nonsense change (p.Gln371Ter), and no pathogenic missense variant at codon 371 is present in ClinVar. The automated PM5 candidate search returned no comparator variants. Details ▾Hide ▴

Evidence considered

PM5 candidate harvesting returned 0 candidates at codon 371
ClinVar contains no pathogenic missense variant at this residue

Sources

pm5_candidatesclinvar ↗

PM6 No de novo occurrence data are available for this variant. PM6 requires observation of a de novo event without confirmation of paternity and maternity. Details ▾Hide ▴

Still missing

No de novo testing performed

PP1 No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴

Still missing

No family segregation data available

PP4 No patient phenotype data were provided for this case. PP4 requires that the proband phenotype or family history is highly specific for the disease entity associated with the gene. Details ▾Hide ▴

Still missing

Patient phenotype and family history not available for review

PP5 This variant is absent from ClinVar. No expert panel or reputable source has classified this variant as pathogenic. The ClinVar search returned no matching variation IDs for NM_133509.4:c.1111C>T. Details ▾Hide ▴

Evidence considered

No ClinVar entry — zero submitters have classified this variant

Sources

clinvar ↗

BA1 The gnomAD v4.1 allele frequency of 4.53 × 10⁻⁶ (0.00045%) is far below the 1% BA1 threshold. This variant is not a common polymorphism. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 4.53e-06 — far below 1% BA1 threshold

Sources

gnomad_v4 ↗

BS1 The gnomAD v4.1 allele frequency of 4.53 × 10⁻⁶ (0.00045%) is far below the 0.3% BS1 threshold. Expected in a rare disease variant. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 4.53e-06 — far below 0.3% BS1 threshold

Sources

gnomad_v4 ↗

BS2 No homozygotes are observed in gnomAD (0/1,324,198 alleles). BS2 requires observation in healthy adults in a homozygous or compound heterozygous state for a fully penetrant dominant disorder. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: 0 homozygotes

Sources

gnomad_v4 ↗

BS3 No well-established functional studies showing no deleterious effect exist for this variant. None of the five full-text publications reviewed tested NM_133509.4:c.1111C>T. While gene-level functional studies (PMID:16778173, PMID:25368520) demonstrate RAD51B involvement in homologous recombination repair, these support a pathogenic role and do not provide benign effect evidence. Details ▾Hide ▴

Evidence considered

No variant-specific benign functional evidence available
Gene-level knockdown studies show RAD51B is required for HR repair and chromosome stability

Sources

PMID:16778173 ↗PMID:25368520 ↗

BS4 No segregation data are available for this variant. BS4 requires lack of segregation with disease in affected family members. Details ▾Hide ▴

Still missing

No family segregation data available

BP2 No data are available regarding trans configuration with a known pathogenic RAD51B variant. BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic variant in a recessive gene. Details ▾Hide ▴

Still missing

No phase information available

BP5 No alternative molecular basis for disease has been identified in this case, and BP5 is typically applied when an alternate cause is confirmed. Additionally, no benign ClinVar classification exists for this variant. Details ▾Hide ▴

Still missing

No data on alternative molecular diagnoses

BP6 The variant is absent from ClinVar; no reputable source has classified it as benign. BP6 requires a benign or likely benign classification from a reputable source. Details ▾Hide ▴

Evidence considered

No ClinVar entry — no benign classification from any source

Sources

clinvar ↗

PS5 This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source. No ClinVar variation ID was identified for NM_133509.4:c.1111C>T. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar — no pathogenic assertion from any submitter

Sources

clinvar ↗

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PM3 N/ASkipped per adjudication instructions (trivially not_applicable — recessive disorder criterion for trans configuration; RAD51B-associated cancer predisposition follows autosomal dominant inheritance). Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped per adjudication instructions (trivially not_applicable — PM4 applies to protein length changes from indels; this variant is a single-nucleotide substitution). Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This variant is a nonsense change, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 (multiple lines of computational evidence support a deleterious effect) is not independently applied to nonsense variants. The molecular consequence — a premature termination codon — already provides direct evidence of a deleterious effect, which is captured by PVS1. SpliceAI predicts no significant splice impact (max delta score = 0.09). REVEL score is not available. BayesDel score of 0.049 is low, reflecting that missense prediction tools are not calibrated for stop-gain variants. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.09 — no splice impact
BayesDel = 0.0487 — low (not calibrated for nonsense variants)
REVEL not available

Sources

spliceai ↗bayesdel

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This variant is itself a truncating (nonsense) change in a gene where LOF is the established mechanism. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASkipped per adjudication instructions (trivially not_applicable — in-frame indels in repeat regions). This variant is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 (multiple lines of computational evidence suggest no impact) is not independently applied to nonsense variants that create a premature termination codon. The molecular consequence — loss of the C-terminal protein sequence and native stop codon — is inherently deleterious. SpliceAI predicts no cryptic splice effect (max delta = 0.09), but BP4 does not apply to truncating variants. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.09 — no cryptic splice effect
BP4 not applicable to nonsense variants

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_133509.4:c.1111C>T is a nonsense (stop-gain) variant, not a synonymous substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: RAD51B
Transcript: NM_133509.4
Coding (HGVS c.): NM_133509.4:c.1111C>T
Protein (HGVS p.): NP_598193.2:p.(Gln371Ter)
GRCh38: chr14:68594559 C>T
GRCh37: chr14:69061276 C>T

Gene diagram

Every interpreted variant in RAD51B, mapped onto the exon structure of NM_133509.4. Select a row to find it on the plot.

RAD51BNM_133509.4

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 RAD51B — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 6 / 1,324,198 alleles AF 4.53e-06 · 0 homozygotes · FAF 2.15e-06

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 4.5e-06 · 6 / 1,324,198 alleles · 0 hom · FAF 2.2e-06

European (non-Finnish)6 / 1,004,812

6e-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= 4.53104e-06; MAF= 0.00045%, 6/1324198 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.97127e-06; MAF= 0.00060%, 6/1004812 alleles, homozygotes = 0); grpmax FAF= 2.15e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -74 bp

0.090

SpliceAI acceptor gainat +55 bp

0.000

SpliceAI donor lossat +147 bp

0.000

SpliceAI donor gainat -486 bp

0.000

Other predictors

REVEL: Not available
BayesDel: 0.049

How the predictions were used

Evidence considered

SpliceAI max delta = 0.09 — no splice impact
BayesDel = 0.0487 — low (not calibrated for nonsense variants)
REVEL not available

Sources

spliceai ↗bayesdel

Evidence considered

SpliceAI max delta = 0.09 — no cryptic splice effect
BP4 not applicable to nonsense variants

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_133509.4:c.1111C>T is a nonsense (stop-gain) variant, not a synonymous substitution. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). BayesDel score = 0.0486889.

5 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

Haploinsufficiency of RAD51B causes centrosome fragmentation and aneuploidy in human cells.

Demonstrates that haploinsufficiency of RAD51B causes mild hypersensitivity to DNA-damaging agents, impaired Rad51 focus formation, increased chromosome aberrations, centrosome fragmentation, and aneuploidy in HCT116 human colon cancer cells. RAD51B knockdown by siRNA in HT1080 cells also leads to centrosome fragmentation.
Does not name this variant
PMID 16778173 ↗
Quoted passage
Here, we show that haploinsufficiency of RAD51B causes mild hypersensitivity to DNA-damaging agents, a mild reduction in sister chromatid exchange, impaired Rad51 focus formation, and an increase in chromosome aberrations. Remarkably, haploinsufficiency of RAD51B leads to centrosome fragmentation and aneuploidy.
Results: RAD51B gene targeting and functional assays throughout
Germline mutation in the RAD51B gene confers predisposition to breast cancer.

First report of a germline RAD51B truncating mutation (c.452+3A>G, splice site) in a family with breast and ovarian cancer. Also identified a likely deleterious missense variant RAD51B c.475C>T (p.Arg159Cys). RAD51B immunohistochemistry of the splice mutation carrier's breast carcinoma showed loss of RAD51B expression.
Does not name this variant
PMID 24139550 ↗
Quoted passage
We identified a RAD51B mutation and a likely deleterious variant in two patients: the RAD51B c.452+3A>G mutation was detected in a breast and ovarian cancer family case and the RAD51B p.Arg159Cys variant was detected in a family with 3 breast cancer cases.
Results para 1; Table 2; Figure 2
RAD51B Activity and Cell Cycle Regulation in Response to DNA Damage in Breast Cancer Cell Lines.

RAD51B siRNA knockdown in breast cancer cell lines (MCF7, T47D, BT549) results in increased sensitivity to DNA-damaging agents (cisplatin, hydroxyurea), reduced homologous recombination repair efficiency (DR-GFP assay), and disrupted cell cycle checkpoint response. RAD51B depletion alters expression of DNA repair and cell cycle genes.
Does not name this variant
PMID 25368520 ↗
Quoted passage
Depletion of RAD51B increases sensitivity to DNA-damaging agents... Inhibition of RAD51B results in reduced efficiency of HR... Depletion of RAD51B leads to differential cell cycle arrest in response to DNA damage agents.
Results: Colony formation, DR-GFP HR assay, cell cycle FACS analysis
Germline RAD51B truncating mutation in a family with cutaneous melanoma.

Whole-exome sequencing of a three-case cutaneous melanoma family identified a novel germline RAD51B nonsense mutation (c.139C>T, p.Arg47*) in two sisters with melanoma. Immunohistochemistry of melanoma tissue showed reduced RAD51B expression, consistent with inactivation. This is the second report of a germline truncating RAD51B mutation. The variant c.1111C>T (Q371*) is not this mutation.
Does not name this variant
PMID 25600502 ↗
Quoted passage
The nonsense mutation in RAD51B exon 3 (c.139C>T, p.Arg47*) was seen as the most likely candidate melanoma predisposition gene due to the supporting literature.
Results para 1–2; Figure 2
Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.

Population-based case-control sequencing of RAD51B, RAD51C, and RAD51D in 3,429 ovarian cancer cases and 2,772 controls identified deleterious RAD51B mutations in only 2 cases (0.06%): G217X and Q219X in cis. One additional RAD51B splicing mutation (854-2A>G) was found in the UK_FOCSS high-risk screening cohort. RAD51B mutations are rare and confer lower ovarian cancer risk than RAD51C/D mutations.
Does not name this variant
PMID 26261251 ↗
Quoted passage
We identified deleterious mutations in two cases for RAD51B, 14 cases and two controls for RAD51C, and 12 cases and one control for RAD51D.
Results: Deleterious RAD51B, RAD51C, and RAD51D Mutations; Table 2; Appendix Table A3

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

gnomAD v4.1 6 / 1,324,198 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.090 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 ↗

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

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 = 0.09). BayesDel score = 0.0486889.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.