Submissions for variant NM_002878.4(RAD51D):c.716G>A (p.Arg239Gln)

gnomAD frequency: 0.00001  dbSNP: rs780921112

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215330	SCV000273249	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-14	criteria provided, single submitter	clinical testing	The p.R239Q variant (also known as c.716G>A), located in coding exon 8 of the RAD51D gene, results from a G to A substitution at nucleotide position 716. The arginine at codon 239 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540949	SCV000651774	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 239 of the RAD51D protein (p.Arg239Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 229883). 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.
Color Diagnostics, LLC DBA Color Health	RCV000215330	SCV000691357	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 239 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 5/276252 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.
Counsyl	RCV000540949	SCV000786408	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2018-04-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000709436	SCV000839178	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001561222	SCV001783777	uncertain significance	not provided	2024-06-24	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; Observed in an individual with breast cancer in published literature (PMID: 35264596); This variant is associated with the following publications: (PMID: 21111057, 14704354, 19327148, 35264596, 36243179)
Myriad Genetics, Inc.	RCV000540949	SCV004017770	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-04-06	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493513	SCV004242783	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000540949	SCV005054035	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-12-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000540949	SCV005640003	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-04-09	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354557	SCV001549203	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The RAD51D p.Arg239Gln variant was not identified in the literature. The variant was identified in dbSNP (ID: rs780921112) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Counsyl, Ambry Genetics, Color and Mendelics). The variant was identified in control databases in 1 of 30972 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 15010 chromosomes (freq: 0.00007), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg239 residue is conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
GenomeConnect - Invitae Patient Insights Network	RCV000540949	SCV001749700	not provided	Breast-ovarian cancer, familial, susceptibility to, 4		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-28-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.