Submissions for variant NM_002878.4(RAD51D):c.899G>A (p.Arg300Gln)

gnomAD frequency: 0.00002  dbSNP: rs761290755

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230796	SCV000287730	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-12-26	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 300 of the RAD51D protein (p.Arg300Gln). This variant is present in population databases (rs761290755, gnomAD 0.005%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29522266, 35264596). ClinVar contains an entry for this variant (Variation ID: 239405). 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.
GeneDx	RCV000587391	SCV000293101	uncertain significance	not provided	2022-10-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Hauke et al., 2018); This variant is associated with the following publications: (PMID: 21111057, 14704354, 19327148, 29522266)
Ambry Genetics	RCV000567475	SCV000667165	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The p.R300Q variant (also known as c.899G>A), located in coding exon 9 of the RAD51D gene, results from a G to A substitution at nucleotide position 899. The arginine at codon 300 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in 2/5,589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This variant was also reported in 4/60,466 breast cancer cases as well as 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Color Diagnostics, LLC DBA Color Health	RCV000567475	SCV000691377	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 300 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. In a large international case-control study, this variant was reported in 4/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 6/251374 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	RCV000587391	SCV000698117	uncertain significance	not provided	2017-04-20	criteria provided, single submitter	clinical testing	Variant summary: The RAD51D c.899G>A (p.Arg300Gln) variant located in the DNA recombination and repair protein Rad51-like, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. This variant was found in 2/121282 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Mendelics	RCV000709430	SCV000839172	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000567475	SCV002534869	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-07	criteria provided, single submitter	curation
Baylor Genetics	RCV000230796	SCV004208082	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-10-16	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000709430	SCV005903084	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-02-18	criteria provided, single submitter	curation	According to the ACMG SVI adaptation criteria we chose this criterion: BP4 (supporting benign): REVEL: 0.319 (<0.4)