Submissions for variant NM_002878.3(RAD51D):c.394G>A (p.Val132Ile) (rs201141245)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164547	SCV000215203	likely benign	Hereditary cancer-predisposing syndrome	2017-07-07	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Other strong data supporting benign classification
Color	RCV000164547	SCV000910748	likely benign	Hereditary cancer-predisposing syndrome	2016-02-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000458927	SCV000784995	uncertain significance	Breast-ovarian cancer, familial 4	2017-03-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000588322	SCV000292678	uncertain significance	not provided	2018-04-19	criteria provided, single submitter	clinical testing	This variant is denoted RAD51D c.394G>A at the cDNA level, p.Val132Ile (V132I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has been observed in at least two individuals with a personal and/or family history of breast cancer and at least two individuals with epithelial ovarian cancer (Thompson 2013, Song 2015, Kraus 2017). RAD51D Val132Ile was observed at an allele frequency of 0.03% (6/24,020) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the RAD51C binding domain (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51D Val132Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA	RCV000164547	SCV000822177	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000588322	SCV000698100	uncertain significance	not provided	2017-04-20	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000458927	SCV000551340	uncertain significance	Breast-ovarian cancer, familial 4	2018-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 132 of the RAD51D protein (p.Val132Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs201141245, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 27616075, 23372765, 26261251). ClinVar contains an entry for this variant (Variation ID: 185178). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
University of Washington Department of Laboratory Medicine,University of Washington	RCV000458927	SCV000886447	likely benign	Breast-ovarian cancer, familial 4	2018-05-09	criteria provided, single submitter	research	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.