Submissions for variant NM_002878.4(RAD51D):c.868C>T (p.Arg290Trp)

gnomAD frequency: 0.00002  dbSNP: rs527964137

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166995	SCV000217816	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	The p.R290W variant (also known as c.868C>T), located in coding exon 9 of the RAD51D gene, results from a C to T substitution at nucleotide position 868. The arginine at codon 290 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457545	SCV000551371	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-11-10	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 290 of the RAD51D protein (p.Arg290Trp). This variant is present in population databases (rs527964137, 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: 187277). 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.
GeneDx	RCV000589564	SCV000570460	uncertain significance	not provided	2024-12-30	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Identified in an individual with breast cancer (PMID: 25186627); This variant is associated with the following publications: (PMID: 33471991, 25186627, 21111057, 14704354, 19327148)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589564	SCV000698115	uncertain significance	not provided	2015-12-07	criteria provided, single submitter	clinical testing	Variant summary: variant affects a non-conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a large size and aromatic Tryptophan (W). 3/4 in silico tools predict neutral outcome for this substitution (SNPs&GO was not considered because of the low reliability index). Variant was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.0049% which does not exceed the maximal expected allele frequency of a disease causing RAD51D allele (0.025%). To our knowledge, the variant was not reported in HBOC spectrum patients and in vitro/vivo studies assessing the functional impact of the variant were not published either at the time of scoring. Due to lack of clinical data and functional studies, the variant was classified as a variant of uncertain significance until more information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000166995	SCV000908945	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 290 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RAD51D-related disorders in the literature. This variant has been identified in 9/282800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589564	SCV002774725	uncertain significance	not provided	2024-10-09	criteria provided, single submitter	clinical testing	The RAD51D c.868C>T (p.Arg290Trp) variant has been reported in the published literature in an individual with breast cancer (PMID: 25186627 (2015)). This variant has also been observed in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.00012 (3/24958 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.
Baylor Genetics	RCV000457545	SCV004200362	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-11-30	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004764778	SCV005374692	likely benign	Hereditary breast ovarian cancer syndrome	2024-08-13	criteria provided, single submitter	curation	According to the ACMG SVI adaptation criteria we chose these criteria: BP4 (supporting benign): REVEL benign strong 0.083, BayesDel noAF benign moderate -0.4677 SpliceAI: 0.01, BS1 (supporting benign): laut Canvig: BS1 ab 0.0000583 (0.00583%), gnomAD V2, cancer free females; wir haben total: 7/107672 => 0,0065%; Latinos: 3/20086 => 0,015%; Africans: 2/9224 => 0,022%; https://canvaruk.org/result/RAD51D/c.868C%3ET(p.Arg290Trp)#ControlF
Fulgent Genetics, Fulgent Genetics	RCV000457545	SCV005639996	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-05-06	criteria provided, single submitter	clinical testing