Submissions for variant NM_002878.4(RAD51D):c.205G>A (p.Ala69Thr)

gnomAD frequency: 0.00001  dbSNP: rs763439048

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486509	SCV000566434	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14704354, 19327148)
Color Diagnostics, LLC DBA Color Health	RCV000579857	SCV000686427	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 69 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 3/251456 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000649685	SCV000771517	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-08-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 69 of the RAD51D protein (p.Ala69Thr). 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. 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. ClinVar contains an entry for this variant (Variation ID: 418972). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. This variant is present in population databases (rs763439048, gnomAD 0.003%).
Ambry Genetics	RCV000579857	SCV001174962	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-16	criteria provided, single submitter	clinical testing	The p.A69T variant (also known as c.205G>A), located in coding exon 3 of the RAD51D gene, results from a G to A substitution at nucleotide position 205. The alanine at codon 69 is replaced by threonine, 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.