Submissions for variant NM_002878.4(RAD51D):c.715C>T (p.Arg239Trp)

gnomAD frequency: 0.00006  dbSNP: rs770250516

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166936	SCV000217755	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-23	criteria provided, single submitter	clinical testing	The p.R239W variant (also known as c.715C>T), located in coding exon 8 of the RAD51D gene, results from a C to T substitution at nucleotide position 715. The arginine at codon 239 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is reported to co-occur with the p.R232* (c.694C>T) pathogenic RAD51D mutation in a proband with ovarian cancer at age 43 (Wickramanyake A et al. Gynecol. Oncol. 2012 Dec;127:552-5). In another family, both alterations were found in a proband with ovarian cancer at age 44 and in four of her healthy siblings (Gutiérrez-Enríquez S et al. Int. J. Cancer. 2014 May;134:2088-97). Both of these alteration are also reported in a third family with two sisters with ovarian cancer at ages 47 and 46 and their three unaffected children (Sanchez-Bermudez AI et al. Eur J Med Genet. 2018 Jun;61(6):355-361). This variant was reported in 1/3429 patients with invasive epithelial ovarian cancer and 0/2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000236062	SCV000292681	uncertain significance	not provided	2024-05-07	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast or ovarian cancer, some of whom are reported to also carry the pathogenic variant RAD51D p.Arg232Ter (PMID: 22986143, 24130102, 26261251, 29409816, 35264596, 35534704, 35980532); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24130102, 22986143, 26261251, 29409816, 35366121, 36243179, 35534704, 19327148, 21111057, 14704354, 35264596, 35980532)
Counsyl	RCV000409739	SCV000488994	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2016-08-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409739	SCV000551328	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 239 of the RAD51D protein (p.Arg239Trp). This variant is present in population databases (rs770250516, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 22986143, 24130102, 26261251, 29409816). ClinVar contains an entry for this variant (Variation ID: 187225). 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) 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.
Mendelics	RCV003491913	SCV000839179	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236062	SCV000888609	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	The RAD51D c.715C>T (p.Arg239Trp) variant has been reported in the published literature in individuals with ovarian cancer (PMID: 26261251 (2015)), including a few who also carried the RAD51D c.694C>T (p.Arg232*) pathogenic variant (PMIDs: 22986143 (2012), 24130102 (2014), 29409816 (2018)). This variant has also been observed in individuals with breast cancer as well as in reportedly healthy individuals (PMIDs: 35264596 (2022), 36243179 (2022), 24130102 (2014), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.00004 (5/126380 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000409739	SCV000895089	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166936	SCV000902844	likely benign	Hereditary cancer-predisposing syndrome	2015-11-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000236062	SCV001151268	uncertain significance	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166936	SCV002534847	likely benign	Hereditary cancer-predisposing syndrome	2021-07-16	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409739	SCV004017754	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-04-06	criteria provided, single submitter	clinical testing	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000236062	SCV001553159	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RAD51D p.Arg239Trp variant was identified in 8 of 10584 proband chromosomes (frequency: 0.0008) from individuals or families with breast or ovarian cancer and was not identified in 5624 control chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Sanchez-Bermudez 2018, Song 2015, Wickramanayake 2012). The variant was also identified in several population studies with a co-occurring pathogenic RAD51D variant (c.694C>T, p.Arg232*) in multiple members of same families (Sanchez-Bermudez 2018, Gutierrez-Enriquez 2013, Wickramanayake 2012). The variant was also identified in dbSNP (ID: rs770250516) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and four other submitters). The variant was identified in control databases in 9 of 271100 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6340 chromosomes (freq: 0.0002), European in 5 of 123902 chromosomes (freq: 0.00004), East Asian in 2 of 18598 chromosomes (freq: 0.0001), and South Asian in 1 of 29868 chromosomes (freq: 0.00003), while the variant was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. The p.Arg239 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.