ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.919G>A (p.Glu307Lys) (rs115031549)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656966 SCV000149730 likely benign not provided 2021-03-07 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25186627, 28864920)
Ambry Genetics RCV000115821 SCV000185235 likely benign Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000989829 SCV000287733 likely benign Breast-ovarian cancer, familial 4 2020-12-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656966 SCV000602170 likely benign not provided 2019-08-14 criteria provided, single submitter clinical testing
Mendelics RCV000709428 SCV000839170 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000656966 SCV000859940 uncertain significance not provided 2018-03-09 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115821 SCV000910718 benign Hereditary cancer-predisposing syndrome 2015-11-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212975 SCV000918142 benign not specified 2018-07-31 criteria provided, single submitter clinical testing Variant summary: RAD51D c.919G>A (p.Glu307Lys) results in a conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was found in 78/277234 control chromosomes in gnomAD, but was observed primarily in the African subpopulation (70/24038 control chromosomes). The frequency within the African control individuals is more than 23-fold above the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer phenotype (0.00013). In addition, this variant has been found in 21/2559 African American women who are 70 years old or older and are cancer-free. These evidence strongly suggests that the variant is a benign polymorphism found primarily in populations of African origin. c.919G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments including uncertain significance (2x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000989829 SCV001140404 uncertain significance Breast-ovarian cancer, familial 4 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354385 SCV001548991 likely benign Malignant tumor of breast no assertion criteria provided clinical testing RAD51D, EXON10, c.919G>A, p.Glu307Lys, Heterozygous, Likely Benign The RAD51D p.Glu307Lys variant was identified in 2 of 4316 proband chromosomes (frequency: 0.0005) from individuals or families with breast cancer (Tung 2015). The variant was also identified in dbSNP (ID: rs115031549) as "With Uncertain Significance allele", in ClinVar with Conflicting interpretations of pathogenicity (as Benign by Integrated Genetics and Colour, as Likely benign by Invitae and Ambry and as Uncertain significance by Mendelics, Quest, GeneDx and EGL Genetics). The variant was identified in control databases in 78 of 277234 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 70 of 24038 chromosomes (freq: 0.003), Other in 1 of 6468 chromosomes (freq: 0.0002), Latino in 7 of 34420 chromosomes (freq: 0.0002), but was not observed in the European Non-Finnish, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Glu307 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. Assessment Date: 2019/07/29

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