Submissions for variant NM_002878.4(RAD51D):c.307A>G (p.Thr103Ala)

gnomAD frequency: 0.00005  dbSNP: rs781378161

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526498	SCV000651730	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 103 of the RAD51D protein (p.Thr103Ala). This variant is present in population databases (rs781378161, 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: 472597). 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.
Ambry Genetics	RCV000564410	SCV000663824	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-05	criteria provided, single submitter	clinical testing	The p.T103A variant (also known as c.307A>G), located in coding exon 4 of the RAD51D gene, results from an A to G substitution at nucleotide position 307. The threonine at codon 103 is replaced by alanine, 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.
Color Diagnostics, LLC DBA Color Health	RCV000564410	SCV000905831	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 103 of the RAD51D protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). 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 5/282706 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.
GeneDx	RCV001779003	SCV002015518	uncertain significance	not provided	2022-05-11	criteria provided, single submitter	clinical testing	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14704354, 21111057)
Baylor Genetics	RCV000526498	SCV005054002	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945290	SCV004773502	uncertain significance	RAD51D-related disorder	2023-11-09	no assertion criteria provided	clinical testing	The RAD51D c.307A>G variant is predicted to result in the amino acid substitution p.Thr103Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-33434423-T-C) and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/472597/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.