ClinVar Genomic variation as it relates to human health

Variant summary: The c.394G>A (p.Val132Ile) in RAD51D gene is a missense change that involves a non-conserved nucleotide. Although the variant is located within the ATP binding site of conserved domain Rad51_DMC1_radA, 4/5 in silico tools predict benign outcome. The variant is present in the large control population dataset of ExAC and gnomAD at a similar frequencies of 0.00007 (9/121398 and 17/277162 chrs tested, respectively), predominantly in individuals of African descent (0.0002884; 3/10404 and 6/24020 chrs tested) which exceeds the maximal expected frequency of a pathogenic allele (0.00012) in this gene. The variant has been reported in at least 1 sporadic brC case (Kraus, 2017) and 2 BrC families without strong evidence for causality (Thompson, 2013; Song, 2015). Lastly, several reputable databases/clinical laboratories cite the variant with classification of VUS but favoring the benign nature of this change. Taking all line of evidence into consideration, the variant was conservatively classified as VUS-Possibly Benign.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

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.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal and/or family history of breast or ovarian cancer and also in unaffected controls (PMID: 23372765, 26261251, 27616075, 30374176, 33471991, 35534704); This variant is associated with the following publications: (PMID: 23372765, 26261251, 27616075, 30374176, 29300386, 31159747, 32426482, 33471991, Giacomazzi2022[preprint], 14704354, 19327148, 21111057, 36243179, 35534704)

The RAD51D variant designated as NM_002878.3:c.394G>A (p.Val132Ile) is classified as likely benign. This variant is listed in ClinVar (Variation ID: 141739) and has been classified as likely benign by another laboratory. Computer software programs (SIFT, Polyphen-2, Align-GVGD) all predict that this variant is likely to be tolerated. In one observed family, this variant was not detected in an affected relativer’s ovarian tumor, which indicates that it is unlikely to be the cause of her ovarian cancer. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about a 3% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter RAD51D function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

In the published literature, this variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 23372765 (2013), 26261251 (2015), 27616075 (2016)). This variant has also been reported in individuals with breast cancer and unaffected individuals in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.00024 (6/24958 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 132 of the RAD51D protein (p.Val132Ile). This variant is present in population databases (rs201141245, gnomAD 0.02%). This missense change has been observed in individual(s) with ‚Äãbreast and/or ovarian cancer and gastric cancer (PMID: 23372765, 26261251, 27616075, 32426482). ClinVar contains an entry for this variant (Variation ID: 185178). 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) performed at Invitae 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.

According to the ACMG SVI adaptation criteria we chose these criteria: BP4 (supporting benign): REVEL Score: 0.229, BS1 (strong benign): TAF: 0.00005963 (gnomad 2.1, non-cancer)

The RAD51D p.Val132Ile variant was identified in 4 of 10,140 proband chromosomes (frequency: 0.0004) from individuals with breast and ovarian cancer and was not identified in 6476 control chromosomes from healthy individuals (Kraus 2017, Thompson 2013, Song 2015). The variant was identified in dbSNP (rs201141245) as “with uncertain significance allele”, in ClinVar (interpreted as "uncertain significance" by Invitae and 4 others, "likely benign" by Ambry Genetics and 3 others). The variant was identified in control databases in 17 of 277,162 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 6 of 24,020 chromosomes (freq: 0.0003), Latino in 4 of 34,418 chromosomes (freq: 0.0001), European in 6 of 126,668 chromosomes (freq: 0.00005), Finnish in 1 of 25,788 chromosomes (freq: 0.00004); it was not observed in the “Other”, Ashkenazi Jewish, East Asian and South Asian populations. The variant was observed in our laboratory in an individual with a likely pathogenic BRCA1 variant (p.Val1833Met). The p.Val132 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Variant interpreted as Uncertain significance and reported on 02-12-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.