Submissions for variant NM_002878.4(RAD51D):c.217G>A (p.Glu73Lys)

gnomAD frequency: 0.00001  dbSNP: rs369946779

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167186	SCV000218022	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	The p.E73K variant (also known as c.217G>A), located in coding exon 3 of the RAD51D gene, results from a G to A substitution at nucleotide position 217. The glutamic acid at codon 73 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475794	SCV000551382	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-04-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 73 of the RAD51D protein (p.Glu73Lys). This variant is present in population databases (rs369946779, gnomAD 0.02%). 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: 187455). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588922	SCV000698092	uncertain significance	not provided	2016-05-27	criteria provided, single submitter	clinical testing	Variant summary: The RAD51D c.217G>A (p.Glu73Lys) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 2/121310 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). One clinical diagnostic laboratory/reputable database classified this variant as a VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000167186	SCV002052091	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 73 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251462 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.
Baylor Genetics	RCV000475794	SCV004200378	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-08-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000588922	SCV005437632	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	Functional studies suggest this variant may result in slightly increased amount of alternatively spliced transcripts (PMID: 34200360); Not observed at significant frequency in large population cohorts (gnomAD); 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: 14704354, 19327148, 34200360)