Submissions for variant NM_002878.4(RAD51D):c.629C>A (p.Ala210Glu)

dbSNP: rs376855484

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475295	SCV000551365	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 210 of the RAD51D protein (p.Ala210Glu). This variant is present in population databases (rs376855484, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and fallopian tube cancer (PMID: 29522266, 33452952). ClinVar contains an entry for this variant (Variation ID: 410563). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAD51D protein function. 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	RCV000485736	SCV000565469	uncertain significance	not provided	2023-09-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.293C>A p.(Ala98Glu); This variant is associated with the following publications: (PMID: 29522266, 21111057, 14704354, 35496736, 33452952, 33471991, 35053526)
Ambry Genetics	RCV000575046	SCV000671941	uncertain significance	Hereditary cancer-predisposing syndrome	2025-02-19	criteria provided, single submitter	clinical testing	The p.A210E variant (also known as c.629C>A), located in coding exon 7 of the RAD51D gene, results from a C to A substitution at nucleotide position 629. The alanine at codon 210 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358) and in a female with high grade serous fallopian tube cancer who carried a second RAD51D variant classified as likely pathogenic (Yang C et al. Breast Cancer Res Treat, 2021 Feb;185:869-877). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000575046	SCV000686476	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-09	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glutamic acid at codon 210 of the RAD51D protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer who also carried the variant RAD51D c.82G>A, (p.Val28Met) that was reported to disrupt RNA splicing (PMID: 33452952), as well as in two individuals affected with breast cancer (PMID: 29522266, 33471991). This variant has been identified in 1/251402 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	RCV000781798	SCV000920127	uncertain significance	not specified	2017-11-03	criteria provided, single submitter	clinical testing	Variant summary: The RAD51D c.629C>A (p.Ala210Glu) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/246188 control chromosomes at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. 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.
Sema4, Sema4	RCV000575046	SCV002534839	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000781798	SCV002550917	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000475295	SCV004200365	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-03-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485736	SCV004220183	uncertain significance	not provided	2023-01-30	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251402 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has been reported in individuals with breast cancer (PMIDs: 29522266 (2018) and 33471991 (2021)) and in an individual with high grade serous fallopian tube cancer however the individual also carried another variant (RAD51D c.82G>A) which was suggested to be the cause of the disease (PMID: 33452952 (2021)).Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000475295	SCV006052604	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-11-03	criteria provided, single submitter	clinical testing