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

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164547	SCV000215203	likely benign	Hereditary cancer-predisposing syndrome	2018-08-06	criteria provided, single submitter	clinical testing	Other strong data supporting benign classification
GeneDx	RCV000588322	SCV000292678	uncertain significance	not provided	2020-10-30	criteria provided, single submitter	clinical testing	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 (Thompson 2013, Song 2015, Kraus 2017, Tsai 2018); This variant is associated with the following publications: (PMID: 23372765, 26261251, 27616075, 30374176, 29300386, 31159747, 32426482)
Invitae	RCV000458927	SCV000551340	uncertain significance	Breast-ovarian cancer, familial 4	2020-10-21	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 observed 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Counsyl	RCV000458927	SCV000784995	uncertain significance	Breast-ovarian cancer, familial 4	2017-03-06	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000164547	SCV000822177	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
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.
Color Health, Inc	RCV000164547	SCV000910748	likely benign	Hereditary cancer-predisposing syndrome	2016-02-22	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000588322	SCV001151270	uncertain significance	not provided	2017-04-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588322	SCV001470090	uncertain significance	not provided	2020-01-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001356158	SCV001551245	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	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.