RAD51D c.619T>C, p.Ser207Pro
NM_002878.4:c.619T>C
Likely Pathogenic
This RAD51D missense variant p.S207P is classified as Likely Pathogenic based on two Moderate criteria (PM2: extremely low population frequency; PM5: novel missense at a residue with known pathogenic changes) and one Supporting criterion (PP3: deleterious computational predictions). No higher‐level or conflicting evidence alters this classification.
ACMG/AMP Criteria Applied
PM2
PM5
PP3
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.619T>C
Protein Change
S207P
Location
Exon 7
(Exon 7 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 207: S207W, S207L
Variant interpretation based on transcript NM_002878.4
Genome Browser
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HGVS InputNM_002878:c.619T>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00106%
Rare
Highest in Population
Remaining individuals
0.0138%
Low Frequency
Global: 0.00106%
Remaining individuals: 0.0138%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282824Alt: 3Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00106%, 3/282824 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0138%, 1/7224 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
3 publications
Likely Pathogenic
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
1 LP
8 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
The p.S207P variant (also known as c.619T>C), located in coding exon 7 of the RAD51D gene, results from a T to C substitution at nucleotide position 619. The serine at codon 207 is replaced by proline, an amino acid with similar properties. This variant was identified in 1/177 individuals with pancreatic ductal adenocarcinoma undergoing multi-gene panel testing (Cremin C et al. Cancer Med, 2020 06;9:4004-4013). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 207 of the RAD51D protein (p.Ser207Pro). This variant is present in population databases (rs372365287, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 229719). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAD51D protein function. This variant disrupts the p.Ser207 amino acid residue in RAD51D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21822267, 22986143, 26845104, 26976419, 28646019). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 missense variant replaces serine with proline at codon 207 in the ATPase domain of the RAD51D protein. The RAD51D ATPase motif is required for resistance to DNA cross-linking agents and for interaction with RAD51C in homologous recombination (PMID: 16236763). This variant is located in the conserved Walker B motif that contributes a glutamic acid residue hydrolyzing ATP in the ATPase domain (PMID: 27941862, 37344587). This variant substitutes the conserved serine (residue 207) adjacent to the catalytic glutamic acid (residue 206) to proline in the RAD51D ATPase domain. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pancreatic ductal adenocarcinoma (PMID: 32255556). This variant has been identified in 3/282824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon (p.Ser207Leu) is considered to be disease-causing (ClinVar Variation ID: 142102), suggesting that serine at this position is important for protein structure and function. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (8 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
ClinVar reports other pathogenic variants at position 207: S207W, S207L
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.847
0.847
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Unknown
PP3 Applied
Yes
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 (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 it is a missense change (S207P), 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 known pathogenic variant but different nucleotide change". The evidence for this variant shows no previously reported pathogenic p.S207P by a different nucleotide. 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". There is no parental genotyping data available. 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". The evidence for this variant shows no functional characterization studies. 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 individuals 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 S207 lies in a mutational hotspot or critical functional 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 MAF of 0.00106% in gnomAD, which is below 0.1%. 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)". There is no phasing or compound heterozygosity data. 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". The evidence for this variant shows a missense change without protein length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
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". The evidence for this variant shows that a different missense change at residue S207 has been reported as pathogenic. Therefore, this criterion is applied at Moderate strength.
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 de novo evidence 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". There are no segregation data. 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". There is insufficient evidence about missense variation tolerance in RAD51D. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
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 (e.g., conservation, splicing impact)". The evidence shows a REVEL score of 0.85, exceeding the 0.75 threshold. Therefore, this criterion is applied at Supporting strength.
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 data are available. 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 (8 VUS vs 1 Likely Pathogenic). 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 (based on population data)". The allele frequency of 0.00106% is below thresholds for BA1. 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 the disorder". The frequency does not exceed expected thresholds. 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 such observations are reported. 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". There are no functional studies showing lack of damaging effect. 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 available. 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". RAD51D disease mechanism includes missense and LoF; insufficient evidence to apply. 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 data on co-occurrence. 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". The variant is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". Computational tools predict deleterious effect (REVEL 0.85). Therefore, this criterion is not applied.
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 alternate molecular diagnosis reported. 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". No reputable benign classification exists. 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". The variant is missense, not synonymous. Therefore, this criterion is not applied.