Submissions for variant NM_002878.4(RAD51D):c.629C>T (p.Ala210Val)

gnomAD frequency: 0.00006  dbSNP: rs376855484

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130714	SCV000185601	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-27	criteria provided, single submitter	clinical testing	The p.A210V variant (also known as c.629C>T), located in coding exon 7 of the RAD51D gene, results from a C to T substitution at nucleotide position 629. The alanine at codon 210 is replaced by valine, an amino acid with similar properties. This alteration has been reported in individuals diagnosed with breast, ovarian, pancreatic and colon cancer (Gutiérrez-Enríquez S et al. Int. J. Cancer. 2014 May; Couch FC et al. J. Clin. Oncol. 2015 Feb;33:304-11134:2088-97; Velázquez C et al. Cancers (Basel), 2020 Aug;12; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Dorling et al. N Engl J Med. 2021 02;384:428-439; Janatova M et al. PLoS ONE. 2015 Jun;10:e0127711; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Chaffee KG et al. Genet Med, 2018 01;20:119-127; Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). 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.
Counsyl	RCV000412230	SCV000489288	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2016-09-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130714	SCV000537602	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 210 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 reported in multiple individuals affected with ovarian cancer (PMID: 24130102, 26057125, 26261251), breast cancer (PMID: 25452441), Lynch syndrome associated cancers and/or polyps (PMID: 25980754, 27978560), and pancreatic cancer (PMID: 28726808). It has also been observed in unaffected individuals (PMID: 33471991; Color internal data). This variant has been identified in 8/282794 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	RCV000412230	SCV000551348	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 210 of the RAD51D protein (p.Ala210Val). This variant is present in population databases (rs376855484, gnomAD 0.006%). This missense change has been observed in individual(s) with ovarian cancer, breast cancer, pancreatic cancer, colon cancer and an individual undergoing Lynch syndrome testing (PMID: 24130102, 25452441, 25980754, 26057125, 26261251, 27978560, 28726808). ClinVar contains an entry for this variant (Variation ID: 141969). 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	RCV000657049	SCV000567621	uncertain significance	not provided	2024-03-28	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 personal and/or family history of ovarian, breast, or other cancers, and also in unaffected controls from a breast cancer study (PMID: 24130102, 25452441, 26057125, 26261251, 25980754, 27978560, 28726808, 32756499, 33471991, 32885271); This variant is associated with the following publications: (PMID: 32322110, 24130102, 26057125, 25452441, 26261251, 25980754, 27978560, 28726808, 32756499, 33471991, 32885271, 21111057, 14704354, 34326862)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657049	SCV000602163	uncertain significance	not provided	2024-02-12	criteria provided, single submitter	clinical testing	The RAD51D c.629C>T (p.Ala210Val) variant has been reported in the published literature in individuals affected with ovarian cancer (PMID: 24130102 (2014), 26057125 (2015), 26261251 (2015)), suspected Lynch syndrome (PMID: 25980754 (2015)), colorectal cancer (PMID: 27978560 (2016)), pancreatic cancer (PMID: 28726808 (2018)), and breast cancer (PMID: 32885271 (2021), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/RAD51D)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/RAD51D)). The frequency of this variant in the general population, 0.000054 (7/129124 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000484961	SCV001338645	uncertain significance	not specified	2020-04-13	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.629C>T (p.Ala210Val) results in a non-conservative amino acid change located in the DNA recombination and repair protein RecA-like, ATP-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 257026 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.629C>T has been reported in the literature in individuals affected with Breast/Ovarian Cancer Syndrome, Lynch syndrome, or pancreatic cancer (Gutierrez-Enrquez_2014, Couch_2015, Yurgelun_2015, Janatova_2015, Song_2015, Pearlman_2016, Chaffee_2018). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000130714	SCV002534840	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV002509237	SCV002819168	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-08-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412230	SCV004017741	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2024-12-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000412230	SCV004200367	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-03-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000657049	SCV004224337	uncertain significance	not provided	2022-08-31	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000412230	SCV005402271	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-12-14	criteria provided, single submitter	clinical testing	The RAD51D c.629C>T (p.Ala210Val) missense change has a maximum subpopulation frequency of 0.005% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with ovarian cancer (PMID: 24130102, 26057125, 26261251). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000412230	SCV005640004	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-04-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354066	SCV001548587	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51D p.Ala210Val variant was identified in 8 of 16,500 proband chromosomes (frequency: 0.0005) from individuals or families with Lynch syndrome, or pancreatic, breast or ovarian cancer and was not identified in 5538 control chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Couch 2015, Yurgelun 2015, Janatova 2015, Song 2015, Pearlman 2017, Chaffee 2018). The variant was identified in dbSNP (rs376855484) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Color, GeneDx, Ambry Genetics and 2 other submitters). The variant was identified in control databases in 8 of 282,794 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 7 of 129,124 chromosomes (freq: 0.00005) and African in 1 of 24,958 chromosomes (freq: 0.00004), while it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The p.Ala210 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.
PreventionGenetics, part of Exact Sciences	RCV004751279	SCV005353842	uncertain significance	RAD51D-related disorder	2024-03-24	no assertion criteria provided	clinical testing	The RAD51D c.629C>T variant is predicted to result in the amino acid substitution p.Ala210Val. This variant has been reported in patients with breast, ovarian, prostate, pancreas and colorectal cancer, although conclusive evidence of pathogenicity was not presented (Gutiérrez-Enríquez et al. 2014. PubMed ID: 24130102; Table S6, Couch et al. 2014. PubMed ID: 25452441; Janatova et al. 2015. PubMed ID: 26057125; Table S4, Bhai et al. 2021. PubMed ID: 34326862). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is listed as uncertain in ClinVar by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/141969/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.