RAD51C c.252G>T, p.Lys84Asn
NM_058216.3:c.252G>T
Variant of Uncertain Significance (VUS)
The RAD51C K84N variant is a missense change with extremely low population frequency (PM2 Moderate) and multiple computational tools predicting a benign effect (BP4 Supporting), alongside a gene mechanism of truncating variants applying BP1 Supporting. No other evidence supports pathogenicity or strong benign classification; thus it remains a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP1
BP4
Genetic Information
Gene & Transcript Details
Gene
RAD51C
Transcript
NM_058216.3
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_058216.2 | Alternative | 9 exons | Forward |
| NM_058216.1 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_058216.3:c.252G>T
Protein Change
K84N
Location
Exon 2
(Exon 2 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 84 in gene RAD51C
Variant interpretation based on transcript NM_058216.3
Genome Browser
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HGVS InputNM_058216:c.252G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000795%
Very Rare
Highest in Population
European (non-Finnish)
0.00176%
Rare
Global: 0.000795%
European (non-Finnish): 0.00176%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251460Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000795%, 2/251460 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00176%, 2/113738 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
4 publications
Uncertain Significance (VUS)
Based on 7 submitter reviews in ClinVar
Submitter Breakdown
6 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
This missense variant replaces lysine with asparagine at codon 84 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 26261251) and in a tumor sample from an individual affected with familial breast cancer (PMID: 35039523). This variant has also been identified in 2/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Variant summary: The RAD51C c.252G>T (p.Lys84Asn) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 126910 control chromosomes. The variant has been reported in one patient with ovarian cancer, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 84 of the RAD51C protein (p.Lys84Asn). This variant is present in population databases (rs786202890, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer or breast cancer (PMID: 26261251, 35039523). ClinVar contains an entry for this variant (Variation ID: 186362). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 84 in gene RAD51C
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.073
0.073
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.60
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (K84N), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: no previously established pathogenic variant results in the same amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: no de novo occurrence data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.' The evidence for this variant shows: no case-control or prevalence data in affected cohorts. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation.' The evidence for this variant shows: no information on location within a known hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.' The evidence for this variant shows: MAF = 0.000795% in gnomAD, indicating extremely low frequency. Therefore, this criterion is applied at Moderate strength because the variant is absent or extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: no data on occurrence in trans with a pathogenic allele. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes as a result of in-frame deletions/insertions in non-repeat region or stop-loss variants.' The evidence for this variant shows: no change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.' The evidence for this variant shows: no other pathogenic missense alterations at residue K84. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo evidence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: the mechanism of disease for RAD51C is primarily loss-of-function, and missense variants are not established as a common mechanism. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' The evidence for this variant shows: REVEL 0.07, CADD 2.6, SpliceAI 0.03 all predict no impact, which is the opposite of PP3. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no specific clinical phenotype or family history provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: ClinVar submissions are uncertain or likely benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.' The evidence for this variant shows: MAF = 0.000795%, far below 5%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder.' The evidence for this variant shows: MAF is extremely low and not greater than expected. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.' The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members of a family.' The evidence for this variant shows: no segregation information. Therefore, this criterion is not applied.
BP1
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which primarily truncating variants are known to cause disease.' The evidence for this variant shows: RAD51C disease mechanism is loss-of-function and this variant is missense. Therefore, this criterion is applied at Supporting strength because the gene’s pathogenic mechanism is truncating variants.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without a known function.' The evidence for this variant shows: not an in-frame indel in a repeat region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: REVEL score 0.07, CADD 2.6, SpliceAI 0.03 all indicate benign impact. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict a benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no such case reporting. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: ClinVar submissions are primarily VUS. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant for which splicing prediction algorithms predict no impact on splicing and the nucleotide is not highly conserved.' The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.