Submissions for variant NM_002878.4(RAD51D):c.407A>G (p.Asp136Gly)

gnomAD frequency: 0.00001  dbSNP: rs768197423

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216846	SCV000276404	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-05	criteria provided, single submitter	clinical testing	The p.D136G variant (also known as c.407A>G), located in coding exon 5 of the RAD51D gene, results from an A to G substitution at nucleotide position 407. The aspartic acid at codon 136 is replaced by glycine, an amino acid with similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod Pathol, 2016 11;29:1381-1389). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000235687	SCV000293768	uncertain significance	not specified	2017-05-02	criteria provided, single submitter	clinical testing	This variant is denoted RAD51D c.407A>G at the cDNA level, p.Asp136Gly (D136G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Asp136Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51D Asp136Gly occurs at a position that is conserved across species and is located in the ATPase domain (Kim 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether RAD51D Asp136Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461662	SCV000551323	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 136 of the RAD51D protein (p.Asp136Gly). This variant is present in population databases (rs768197423, gnomAD 0.02%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 232305). 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 expected to disrupt RAD51D protein function with a positive 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.
Color Diagnostics, LLC DBA Color Health	RCV000216846	SCV000691338	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 136 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 been reported in an individual affected with endometrial cancer (PMID: 27443514). This variant has been identified in 8/251468 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	RCV000461662	SCV004200399	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998467	SCV005623965	uncertain significance	not provided	2024-06-10	criteria provided, single submitter	clinical testing	The RAD51D c.407A>G (p.Asp136Gly) variant has been reported in the published literature in an individual with endometrial cancer (PMID: 27443514 (2016)) and in a reportedly healthy individual (PMID: 31206626 (2019)). The frequency of this variant in the general population, 0.00023 (8/34592 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.