ClinVar Genomic variation as it relates to human health

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 missense variant replaces serine with proline at codon 207 of the RAD51D protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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 position (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. 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.

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). Advanced 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 at Invitae 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with pancreatic ductal adenocarcinoma who also harbored missense variants in other potentially relevant genes (PMID: 32255556); This variant is associated with the following publications: (PMID: 21111057, 14704354, 16717288, 32255556)

A likely pathogenic mutation was detected in the RAD51D gene (c.283T>C). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 95 of the RAD51D protein (p.Ser95Pro). 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). Computational prediction suggests that this variant may have deleterious impact on protein structure and function . This variant disrupts the p.Ser95 amino acid residue in RAD51D. A different variant affecting the same codon position (p.Ser95Leu) is considered to be disease-causing (ClinVar variation ID: 142102), suggesting that serine at this position is important for protein structure and function (PMID: 21822267, 22986143, 26845104, 26976419, 28646019). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Pathogenic mutations in the RAD51D gene are associated with Breast-ovarian cancer, familial, susceptibility to, 4 (OMIM 614291 ).