Submissions for variant NM_002878.4(RAD51D):c.865G>A (p.Gly289Ser)

gnomAD frequency: 0.00001  dbSNP: rs587782129

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130672	SCV000185558	likely benign	Hereditary cancer-predisposing syndrome	2019-03-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462688	SCV000551343	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 289 of the RAD51D protein (p.Gly289Ser). This variant is present in population databases (rs587782129, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 30111881). ClinVar contains an entry for this variant (Variation ID: 141945). 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.
GeneDx	RCV000480701	SCV000569950	uncertain significance	not provided	2024-05-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Identified in an individual with personal and family history of breast cancer (PMID: 30111881); This variant is associated with the following publications: (PMID: 27397505, 21111057, 14704354, 19327148, 36243179, 30111881)
Color Diagnostics, LLC DBA Color Health	RCV000130672	SCV000908946	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	[draft report note] This missense variant replaces glycine with serine at codon 289 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 observed in an individual affected with familial breast cancer (PMID: 30111881). This variant has been identified in 3/251434 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194378	SCV001363870	uncertain significance	not specified	2019-01-15	criteria provided, single submitter	clinical testing	Variant summary: The variant, RAD51D c.865G>A (p.Gly289Ser) results in a non-conservative amino acid change located in the c-terminus of DNA recombination and repair protein Rad51-like. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246204 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.865G>A has been reported in the literature in an individual affected with breast cancer (Konstanta_2018). This report, however does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one classified as likely benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.