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RAD51Cc.493A>GUncertain significance
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Variant interpretation report

RAD51C c.493A>G, p.(Met165Val)

NM_058216.3:c.493A>G NP_478123.1:p.(Met165Val) 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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_058216.3:c.493A>G is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (overall AF = 0.00012%, 2/1,614,182 alleles; highest subpopulation AF = 0.0016% in Finnish), well below the PM2 threshold of <0.1%.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence predict no impact: REVEL score 0.046 (well below the 0.5 pathogenic threshold), BayesDel score -0.475 (negative/benign prediction), and SpliceAI max delta score 0.00 (no predicted splicing alteration).

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, BP4 supporting; 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
4 reported laboratory submissions

3 Uncertain significance · 1 Benign.

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.

27 criteria with recorded statuses: 2 met · 10 not met · 12 not assessed · 3 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

NM_058216.3:c.493A>G (p.Met165Val) in RAD51C is a missense variant in exon 3. The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification for RAD51C (version 1.0.0) does not provide criterion-level rules; assessment follows generic ACMG/AMP 2015 guidelines.

This variant is absent from gnomAD v2.1 and gnomAD-Canada and is extremely rare in gnomAD v4.1 (overall allele frequency 0.00012%, 2/1,614,182 alleles), meeting PM2 at supporting strength.

Multiple in silico tools predict a benign effect: REVEL score 0.046, BayesDel score -0.475, and SpliceAI max delta 0.00, meeting BP4 at supporting strength.

ClinVar reports this variant as uncertain significance (3 clinical laboratories) and benign (1 clinical laboratory). No expert panel classification is available. No publication identified mentions this specific variant.

No functional studies, segregation data, case-control analyses, or de novo observations were identified for this variant. The variant has not been characterized experimentally.

With PM2 (supporting) and BP4 (supporting) as the only applicable criteria, the evidence is balanced but insufficient for a definitive classification; the variant remains a variant of uncertain significance.

Met · 2

PM2 SupportingNM_058216.3:c.493A>G is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (overall AF = 0.00012%, 2/1,614,182 alleles; highest subpopulation AF = 0.0016% in Finnish), well below the PM2 threshold of <0.1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: AF = 0.00012% (2/1
  • 614
  • 182 alleles
  • 0 homozygotes).
  • gnomAD-Canada v1.0: absent.
  • All population AFs well below PM2 threshold of <0.1%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence predict no impact: REVEL score 0.046 (well below the 0.5 pathogenic threshold), BayesDel score -0.475 (negative/benign prediction), and SpliceAI max delta score 0.00 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.046 (benign
  • below 0.5 threshold).
  • BayesDel: -0.475 (benign
  • negative score).
  • SpliceAI: max delta = 0.00 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 10 · evaluated, threshold not reached

PS3 No well-established functional studies demonstrating a deleterious effect for NM_058216.3:c.493A>G were identified. OncoKB reports no variant-specific functional evidence. No publication mentions this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional data available.
Still missing
  • Functional characterization of p.Met165Val has not been performed.
Sources
oncokb ↗
PM1 Residue Met165 is not located in a known mutational hotspot or well-established critical functional domain. Hotspot analysis confirmed no statistically significant enrichment at this position. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: residue not significant
  • exact variant not listed in known cancer hotspots.
PM5 No pathogenic missense variant at the same residue (Met165) with a different amino acid change was identified in ClinVar for PM5 comparator analysis. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found zero same-residue comparator variants.
PP3 Multiple in silico tools predict a benign effect: REVEL score 0.046 (well below 0.5 damaging threshold), BayesDel score -0.475 (negative/benign), and SpliceAI max delta = 0.00 (no splicing impact). These findings support a benign interpretation rather than PP3. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.046 (benign range).
  • BayesDel: -0.475 (benign).
  • SpliceAI max delta: 0.00 (no splice effect predicted).
  • HCI prior: gene not supported in HCI database.
Sources
revelbayesdelspliceai ↗
PP5 This variant is not classified as pathogenic by any reputable source. ClinVar reports uncertain significance (3 submitters) and benign (1 submitter). No expert panel classification is available. Details ▾Hide ▴
Evidence considered
  • ClinVar: 3 VUS
  • 1 Benign. No pathogenic classification from any reputable source.
Sources
clinvar ↗
BA1 This variant is extremely rare in population databases (gnomAD v4.1 AF = 0.00012%), far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 overall AF = 0.00012%
  • well below 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 This variant is extremely rare in population databases (gnomAD v4.1 AF = 0.00012%), far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 overall AF = 0.00012%
  • well below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BP1 RAD51C is a tumor suppressor gene in which both missense and truncating variants are established disease mechanisms; a missense change in this gene does not meet BP1, which requires that the gene cause disease primarily through truncating variants. Details ▾Hide ▴
Evidence considered
  • RAD51C loss-of-function mechanism is supported
  • but pathogenic missense variants are also well-documented in this gene (e.g.
  • in Fanconi anemia and HBOC). Gene does not meet the 'primarily truncating' requirement.
BP6 One ClinVar submitter (Ambry Genetics) classifies this variant as benign, but this is a single submitter without expert panel review. Generic BP6 requires a reputable source classification; a single clinical laboratory report does not meet this threshold. Details ▾Hide ▴
Evidence considered
  • Ambry Genetics (SCV000667122): Benign
  • criteria provided
  • single submitter — insufficient for BP6 without expert panel consensus.
Sources
clinvar ↗
PS5 ClinVar reports uncertain significance (3 clinical laboratories) and benign (1 laboratory); no reputable source classifies this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: 3 submitters = Uncertain significance
  • 1 submitter = Benign. No expert panel or reputable source reports as pathogenic.
Sources
clinvar ↗

Not assessed · 12 · no assessment recorded

PS1 No prior pathogenic variant at the same amino acid position (Met165) identified in ClinVar or VCEP materials for comparison. Details ▾Hide ▴
Still missing
  • No same-residue pathogenic comparator variant available for PS1 assessment.
PS2 No de novo observation data with confirmed maternity/paternity available for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports identified in ClinVar submissions or literature.
PS4 No case-control studies or aggregate patient data reporting NM_058216.3:c.493A>G prevalence in affected versus unaffected individuals were identified. Details ▾Hide ▴
Still missing
  • No case-control or cohort data available for this variant.
PM6 No de novo observation (with or without confirmed parentage) has been reported for NM_058216.3:c.493A>G. Details ▾Hide ▴
Still missing
  • No de novo reports identified in ClinVar or literature.
PP1 No co-segregation data available for NM_058216.3:c.493A>G in affected families. Details ▾Hide ▴
Still missing
  • No segregation studies identified.
PP2 RAD51C is a moderate-penetrance cancer predisposition gene with both missense and truncating pathogenic variants. No VCEP-specific PP2 rule is available, and insufficient data exist to determine whether RAD51C has a low rate of benign missense variation to meet generic PP2. Details ▾Hide ▴
Still missing
  • No gene-specific benign missense constraint data available for PP2 assessment.
PP4 No patient phenotype or clinical data specific to NM_058216.3:c.493A>G carriers were identified for phenotype-specificity assessment. Details ▾Hide ▴
Still missing
  • No phenotype data available for variant carriers.
BS2 No data on observation of NM_058216.3:c.493A>G in healthy adults in the absence of disease phenotype were identified. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data available.
BS3 No well-established functional studies demonstrating no deleterious effect for NM_058216.3:c.493A>G were identified. Details ▾Hide ▴
Still missing
  • No functional studies (damaging or benign) available for this variant.
BS4 No segregation data available to demonstrate lack of co-segregation with disease. Details ▾Hide ▴
Still missing
  • No segregation studies identified.
BP2 No data on observation of NM_058216.3:c.493A>G in trans with a known pathogenic variant were identified. Details ▾Hide ▴
Still missing
  • No phase data available.
BP5 No data on observation of NM_058216.3:c.493A>G in a case where an alternative molecular basis for disease was identified. Details ▾Hide ▴
Still missing
  • No alternative-molecular-basis data available.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot a null variant; missense substitution NM_058216.3:c.493A>G (p.Met165Val) does not fall into PVS1 buckets (nonsense, frameshift, or canonical splice consensus). Details ▾Hide ▴

No further detail was recorded.

BP3 N/AIn-frame deletions/insertions in non-repeat regions are not applicable to this substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_058216.3:c.493A>G is a missense variant (p.Met165Val), not a synonymous variant. BP7 applies exclusively to synonymous variants with no predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
RAD51C
Transcript
NM_058216.3
Coding (HGVS c.)
NM_058216.3:c.493A>G
Protein (HGVS p.)
NP_478123.1:p.(Met165Val)
GRCh38
chr17:58696781 A>G
GRCh37
chr17:56774142 A>G
ClinVar
482171

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 2 / 1,614,182 alleles AF 1.24e-06 · 0 homozygotes
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 / 1,614,182 alleles · 0 hom
European (Finnish)1 / 64,036 1.6e-05
European (non-Finnish)1 / 1,180,030 8.5e-07
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, 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= 1.23902e-06; MAF= 0.00012%, 2/1614182 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 1.56162e-05; MAF= 0.00156%, 1/64036 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -36 bp
0.000
SpliceAI acceptor gainat -88 bp
0.000
SpliceAI donor lossat -36 bp
0.000
SpliceAI donor gainat +78 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
0.046
BayesDel
-0.475

How the predictions were used

BP4 SupportingMultiple lines of computational evidence predict no impact: REVEL score 0.046 (well below the 0.5 pathogenic threshold), BayesDel score -0.475 (negative/benign prediction), and SpliceAI max delta score 0.00 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.046 (benign
  • below 0.5 threshold).
  • BayesDel: -0.475 (benign
  • negative score).
  • SpliceAI: max delta = 0.00 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico tools predict a benign effect: REVEL score 0.046 (well below 0.5 damaging threshold), BayesDel score -0.475 (negative/benign), and SpliceAI max delta = 0.00 (no splicing impact). These findings support a benign interpretation rather than PP3. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.046 (benign range).
  • BayesDel: -0.475 (benign).
  • SpliceAI max delta: 0.00 (no splice effect predicted).
  • HCI prior: gene not supported in HCI database.
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_058216.3:c.493A>G is a missense variant (p.Met165Val), not a synonymous variant. BP7 applies exclusively 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 = 0.046. BayesDel score = -0.475232.

6 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.
    ACMG/AMP 2015 standards and guidelines for sequence variant interpretation. NM_058216.3:c.493A>G (RAD51C p.Met165Val) was not identified in this paper.
    Does not name this variant
    PMID 25741868 ↗
  • The emerging landscape of breast cancer susceptibility.
    Stratton MR et al. · 2008
    Review of breast cancer susceptibility genes (BRCA1, BRCA2, CHEK2, ATM, BRIP1, PALB2). NM_058216.3:c.493A>G (RAD51C p.Met165Val) was not identified in this paper.
    Does not name this variant
    PMID 18163131 ↗
  • ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.
    2009
    ACOG practice bulletin on hereditary breast and ovarian cancer syndrome, focused on BRCA1/BRCA2 management. NM_058216.3:c.493A>G (RAD51C p.Met165Val) was not identified in this paper.
    Does not name this variant
    PMID 19305347 ↗
  • NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
    NSGC practice guideline for risk assessment and genetic counseling for hereditary breast and ovarian cancer. NM_058216.3:c.493A>G (RAD51C p.Met165Val) was not identified in this paper.
    Does not name this variant
    PMID 23188549 ↗
  • ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
    ACMG policy statement on secondary findings in clinical genome-scale sequencing. NM_058216.3:c.493A>G (RAD51C p.Met165Val) was not identified in this paper.
    Does not name this variant
    PMID 25356965 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi
    Cancer Genetics Risk Assessment and Counseling (PDQ) health professional summary. NM_058216.3:c.493A>G (RAD51C p.Met165Val) was not identified in this paper.
    Does not name this variant
    PMID 26389258 ↗

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

gnomAD v4.1 2 / 1,614,182 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 3 Uncertain significance · 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 ↗
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

This variant is present in gnomAD v4.1 (AF= 1.23902e-06; MAF= 0.00012%, 2/1614182 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 1.56162e-05; MAF= 0.00156%, 1/64036 alleles, homozygotes = 0).

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 (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 482171)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.046. BayesDel score = -0.475232.

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.