Submissions for variant NM_002878.4(RAD51D):c.164G>A (p.Arg55Gln)

gnomAD frequency: 0.00002  dbSNP: rs151198586

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217170	SCV000273742	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	The p.R55Q variant (also known as c.164G>A), located in coding exon 3 of the RAD51D gene, results from a G to A substitution at nucleotide position 164. The arginine at codon 55 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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.
GeneDx	RCV000235863	SCV000294069	uncertain significance	not provided	2023-02-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31159747, 21111057, 14704354, 19327148, 32885271)
Color Diagnostics, LLC DBA Color Health	RCV000217170	SCV000537563	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 55 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282618 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	RCV000459023	SCV000551357	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-19	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 55 of the RAD51D protein (p.Arg55Gln). This variant is present in population databases (rs151198586, gnomAD 0.005%). 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: 230266). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
GeneKor MSA	RCV000217170	SCV000822175	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000709451	SCV000839195	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000217170	SCV002534775	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701283	SCV005202333	uncertain significance	not specified	2024-07-29	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.164G>A (p.Arg55Gln) results in a conservative amino acid change located in the RAD51D, N-terminal domain (IPR048943) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251256 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.164G>A has been reported in the literature as a VUS in settings of multigene panel testing in individuals suspected of a cancer predisposition syndrome, including Hereditary Breast And Ovarian Cancer Syndrome (e.g. Tsaousis_2019, Kwong_2020) . These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31159747, 32068069). ClinVar contains an entry for this variant (Variation ID: 230266). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000459023	SCV005641838	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-08	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358378	SCV001554093	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51D p.Arg55Gln variant was not identified in the literature. The variant was identified in dbSNP (ID: rs151198586) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and three other submitters). The variant was identified in control databases in 3 of 277022 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 126604 chromosomes (freq: 0.000008), East Asian in 1 of 18864 chromosomes (freq: 0.00005), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, and Finnish populations. The p.Arg55 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.