Submissions for variant NM_002878.4(RAD51D):c.835G>A (p.Asp279Asn)

dbSNP: rs765271127

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213661	SCV000275805	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-03	criteria provided, single submitter	clinical testing	The p.D279N variant (also known as c.835G>A), located in coding exon 9 of the RAD51D gene, results from a G to A substitution at nucleotide position 835. The aspartic acid at codon 279 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well 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.
GeneDx	RCV000484011	SCV000569682	uncertain significance	not provided	2016-03-21	criteria provided, single submitter	clinical testing	This variant is denoted RAD51D c.835G>A at the cDNA level, p.Asp279Asn (D279N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant has been reported in at least one individual with a Lynch-syndrome associated tumor and/or colon polyps (Yurgelun 2015). RAD51D Asp279Asn 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 Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. RAD51D Asp279Asn occurs at a position that is not conserved and is located in the ATPase domain (Kim 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether RAD51D Asp279Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000213661	SCV000686492	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 279 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 been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 5/251450 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	RCV000649693	SCV000771525	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 279 of the RAD51D protein (p.Asp279Asn). This variant is present in population databases (rs765271127, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer, Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754, 34326862). ClinVar contains an entry for this variant (Variation ID: 231837). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321550	SCV004026731	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing