RAD51D c.771C>T, p.Ser257=
NM_002878.4(RAD51D):c.771C>T
COSM10445688
Population Frequency
0.058%
Common
ClinVar Classification
Likely Benign
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
1 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
RAD51D
Transcript
NM_002878.4
MANE Select
Total Exons
10
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_002878.2 | Alternative | 10 exons | Reverse |
| NM_002878.3 | RefSeq Select | 10 exons | Reverse |
Variant Details
HGVS Notation
NM_002878.4(RAD51D):c.771C>T
Protein Change
S257=
Location
Exon 9
(Exon 9 of 10)
5'
Exon Structure (10 total)
3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM10445688
Variant interpretation based on transcript NM_002878.4
Clinical Evidence
Global Frequency
0.058%
Common
Highest in Population
African/African American
0.597%
Common
Global: 0.058%
African/African American: 0.597%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 282698
Alt: 164
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.058%, 164/282698 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.597%, 149/24960 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Benign (7 clinical laboratories) and as Likely benign (3 clinical laboratories).
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
Functional Studies
Summary
The variant in RAD51D has not been functionally characterized.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows a synonymous change (S257=) with no effect on protein function. Therefore, this criterion is not applied at Not Applied strength because the variant is not a loss‐of‐function variant.
PS1
PS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but with a different nucleotide change'. The evidence for this variant does not indicate that the same amino acid change has been previously established as pathogenic via an alternate nucleotide change. Therefore, PS1 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'. There is no evidence indicating a de novo occurrence for this variant, so PS2 is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN Pre-processing guidelines, the finding for PS3 is: 'The variant in RAD51D has not been functionally characterized.' The evidence shows a lack of well-established functional studies demonstrating a damaging effect. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PS4 is: 'Prevalence in affected individuals is significantly increased compared with controls'. The evidence does not show an increased prevalence in affected individuals versus controls. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant does not indicate location in a mutational hot spot or critical functional domain. Therefore, PM1 is not applied.
PM2
PM2 (Moderate)
According to Standard ACMG guidelines, PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows an extremely rare minor allele frequency (MAF = 0.058% in gnomAD and low across populations), which supports application of PM2 at Moderate strength.
PM3
PM3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. There is no evidence that this variant is observed in trans with another pathogenic variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The variant in question is synonymous and does not result in a protein length change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence shows that this is a synonymous variant, not a missense change, so PM5 is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. There is no evidence suggesting de novo occurrence for this variant, hence PM6 is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PP1 is: 'Co-segregation with disease in multiple affected family members'. There is no segregation evidence provided for this variant. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 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'. Since the variant is synonymous and not missense, PP2 is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The evidence from in silico predictors for this variant is neutral or mixed and does not support a deleterious effect; hence, PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. No specific phenotype or family history data has been provided that would support PP4. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The reputable sources have reported the variant as benign, not pathogenic, so PP5 is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The allele frequency for this variant is extremely low (MAF = 0.058%), thereby BA1 is not met and not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence shows a very low allele frequency for this variant; thus, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. There is no evidence provided that sufficiently demonstrates this criterion for the variant, so BS2 is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The available evidence does not include well-established functional studies demonstrating no damaging effect, therefore BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BS4 is: 'Lack of segregation in affected family members'. There is no segregation data provided for this variant, so BS4 is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP1 is: 'Missense variant in a gene where only loss-of-function mutations cause disease'. Since this variant is synonymous rather than missense, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. There is no evidence that this variant is observed in trans or in cis with a pathogenic variant, therefore BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The variant in question is not an in-frame deletion/insertion; therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to Standard ACMG guidelines, BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows that multiple computational tools, including SpliceAI (which reported a maximum score of 0), predict no impact on splicing or protein function. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. There is no evidence that this variant is found in a case where another molecular basis for disease exists. Therefore, BP5 is not applied.
BP6
BP6 (Supporting)
According to Standard ACMG guidelines, BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence indicates that multiple clinical laboratories have reported this variant as Benign or Likely Benign in ClinVar. Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Supporting)
According to Standard ACMG guidelines, BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence shows that the variant is synonymous (S257=) and SpliceAI predicts no impact on splicing (maximum score of 0). Therefore, BP7 is applied at Supporting strength.