RAD51D c.493C>T, p.Arg165Trp
NM_002878.4:c.493C>T
COSMIC ID: COSM4721160, COSM9883004
Variant of Uncertain Significance (VUS)
The RAD51D c.493C>T (p.R165W) variant is a rare missense change with multiple in silico tools predicting benign impact (BP4) but lacks functional, segregation, and case-control evidence. It meets PM2 (moderate) for rarity but no additional pathogenic criteria. Conflicting database assertions preclude PP5. The combined evidence is insufficient for pathogenic or benign classification, resulting in a final determination of Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PM2
BP4
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:c.493C>T
Protein Change
R165W
Location
Exon 6
(Exon 6 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 165 in gene RAD51D
Alternate Identifiers
COSM4721160, COSM9883004
Variant interpretation based on transcript NM_002878.4
Genome Browser
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HGVS InputNM_002878:c.493C>T
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Clinical Data
Global Frequency
0.00466%
Rare
Highest in Population
African/African American
0.0123%
Low Frequency
Global: 0.00466%
African/African American: 0.0123%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 279074Alt: 13Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00466%, 13/279074 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.0123%, 3/24306 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
8 publications
Likely Pathogenic
Based on 15 submitter reviews in ClinVar
Submitter Breakdown
1 LP
13 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (8)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 165 of the RAD51D protein (p.Arg165Trp). This variant is present in population databases (rs544654228, gnomAD 0.01%). This missense change has been observed in individual(s) with RAD51D-related conditions (PMID: 31159747, 34284872). ClinVar contains an entry for this variant (Variation ID: 127891). 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 RAD51D 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.
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Variant summary: RAD51D c.493C>T (p.Arg165Trp) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain; DNA recombination and repair protein RecA-like, ATP-binding domain; AAA+ ATPase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 259332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome (4.6e-05 vs 0.00013), allowing no conclusion about variant significance. c.493C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Dominguez-Valentin_2018 and Krivokuca_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (ATM c.9139C>T, p.Arg3047Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21822267, 26261251, 29371908, 34284872). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=9) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (13 clinical laboratories) and as Likely benign (1 clinical laboratories) and as Likely pathogenic (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 165 in gene RAD51D
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.29
0.29
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: 5.83
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
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 (LoF) is a known mechanism of disease". The evidence for this variant shows it is a missense change (R165W), 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 but different nucleotide change". The evidence for this variant shows no previously established pathogenic variant results in R165W. 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". No parental testing or de novo information is available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". No functional studies have been performed for R165W. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". No case-control or prevalence data in affected cohorts are available. 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 or well-established functional domain without benign variation". There is no evidence that R165 is within a mutational 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)". The evidence for this variant shows a gnomAD MAF of 0.00466%, below the 0.1% threshold for dominant disorders. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders". RAD51D-associated disease is not autosomal recessive, and no trans observations are reported. 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 due to in-frame deletions/insertions or stop-loss variants". This is a single amino acid substitution without length change. 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 pathogenic missense change has been seen". There are no known pathogenic variants at residue R165. 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". No evidence of de novo occurrence is available. 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". No segregation data are 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". RAD51D pathogenic variants are predominantly loss-of-function, and missense is 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/gene product". Computational tools (CADD=5.83, REVEL=0.29, SpliceAI=0.02) do not predict a deleterious effect. 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 highly specific for a disease with a single genetic etiology". No detailed phenotype or family history is 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 reports variant as pathogenic, but without accessible evidence". ClinVar submissions are conflicting (Uncertain, Likely benign, Likely pathogenic), undermining reliability. 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 too high for the disorder". The variant MAF of 0.00466% is well below the 5% threshold. 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 variant frequency is below any disease-specific maximum credible allele frequency. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". No data confirm the variant in healthy, phenotyped individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". No functional assays are 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 family members". No segregation studies are reported. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". While LOF is the primary mechanism for RAD51D, evidence is insufficient to assert that all missense variants are benign. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". No such observations exist for this variant. 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 known function". This is a missense substitution, not an in-frame indel. 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 shows a low CADD score (5.83), REVEL score (0.29), and SpliceAI (0.02) predicting no splicing 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". No such case reports exist. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". ClinVar submissions are conflicting and not solely benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". This is a missense variant. Therefore, this criterion is not applied.