ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.796C>T (p.Arg266Cys) (rs587781813)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130084 SCV000184912 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing The p.R266C variant (also known as c.796C>T), located in coding exon 9 of the RAD51D gene, results from a C to T substitution at nucleotide position 796. The arginine at codon 266 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in the literature in individuals affected with breast and/or ovarian cancer<span style="color: rgb(33, 33, 33); font-family: "source sans pro", "helvetica neue", helvetica, roboto, arial, sans-serif; font-size: 13.6px;"> (Thompson ER et al. PLoS ONE, 2013 Jan;8:e54772; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Konstanta I et al. J. Hum. Genet., 2018 Nov;63:1149-1158; Singh J et al. Breast Cancer Res. Treat., 2018 Jul;170:189-196; Krivokuca A et al. J. Hum. Genet., 2019 Apr;64:281-290; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well 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 RCV000255993 SCV000321930 uncertain significance not provided 2021-08-30 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with breast and/or ovarian cancer (Thompson 2013, Hauke 2018, Konstanta 2018, Singh 2018, Krivokuca 2019, Tsaousis 2019); This variant is associated with the following publications: (PMID: 19327148, 14704354, 21111057, 29470806, 30651582, 31159747, 30111881, 29522266, 25775023, 23372765)
Counsyl RCV000411407 SCV000489353 uncertain significance Breast-ovarian cancer, familial 4 2016-09-27 criteria provided, single submitter clinical testing
Invitae RCV000411407 SCV000551380 likely benign Breast-ovarian cancer, familial 4 2020-12-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130084 SCV000686488 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-03 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 266 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 individuals affected with breast and ovarian cancer (PMID: 23372765, 29522266, 30111881, 30651582). This variant has also been identified in 46/282806 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.
PreventionGenetics,PreventionGenetics RCV000255993 SCV000806588 uncertain significance not provided 2017-10-02 criteria provided, single submitter clinical testing
GeneKor MSA RCV000130084 SCV000822184 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255993 SCV000888611 uncertain significance not provided 2019-06-12 criteria provided, single submitter clinical testing
Mendelics RCV000411407 SCV001140411 uncertain significance Breast-ovarian cancer, familial 4 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193713 SCV001362752 likely benign not specified 2019-05-23 criteria provided, single submitter clinical testing Variant summary: RAD51D c.796C>T (p.Arg266Cys) 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 0.00018 in 251416 control chromosomes, predominantly at a frequency of 0.00085 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.796C>T, has been reported in the literature in individuals affected with breast and/or ovarian cancer (Thompson_2013, Lu_2015, Konstanta_2018, Krivokuca_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant eight times as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center RCV000411407 SCV001440342 uncertain significance Breast-ovarian cancer, familial 4 2019-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255993 SCV001446447 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000255993 SCV000986823 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 05/07/2018 by GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357548 SCV001553048 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing RAD51D, EXON9, c.796C>T, p.Arg266Cys, Heterozygous, Uncertain Significance The RAD51D p.Arg266Cys variant was identified in 3 of 16,144 proband chromosomes (frequency: 0.0002) from individuals with breast or ovarian cancer and was not identified in 5310 control chromosomes from healthy individuals (Thompson 2013, Konstanta 2018, Hauke 2018). The variant was identified in dbSNP (rs587781813) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and 6 other submitters). The variant was identified in control databases in 42 of 277,160 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24,030 chromosomes (freq: 0.00008), Other in 2 of 6466 chromosomes (freq: 0.0003), European in 14 of 126,688 chromosomes (freq: 0.0001), and South Asian in 24 of 30,782 chromosomes (freq: 0.0008); it was not observed in the Latino, Ashkenazi Jewish, East Asian or Finnish populations. The p.Arg266 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 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.

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