ClinVar Miner

Submissions for variant NM_001142571.2(RAD51D):c.755G>A (p.Arg252Gln) (rs28363283)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212966 SCV000171274 benign not specified 2014-02-11 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000127695 SCV000213965 benign Hereditary cancer-predisposing syndrome 2014-08-07 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV000205175 SCV000261683 benign Breast-ovarian cancer, familial 4 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000205175 SCV000488478 likely benign Breast-ovarian cancer, familial 4 2016-06-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212966 SCV000602165 benign not specified 2017-06-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000127695 SCV000686481 benign Hereditary cancer-predisposing syndrome 2014-12-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212966 SCV000806584 benign not specified 2017-06-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000760068 SCV000889831 benign not provided 2017-06-28 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000127695 SCV000788208 likely benign Hereditary cancer-predisposing syndrome 2017-09-13 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357198 SCV001552586 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The RAD51D p.Arg232Gln variant was identified in 16 of 10424 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer, ovarian cancer, primary myelofibrosis or lynch syndrome and was not identified in 2120 control chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Loveday 2011, Pratz 2016, Tung 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs28363283) as "With other allele", and in ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Color Genomics, Quest Diagnostics Nichols Institute San Juan Capistrano; as likely benign by Counsyl). The variant was not identified in the Cosmic database. The variant was identified in control databases in 418 of 271350 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 328 of 23508 chromosomes (freq: 0.01), Other in 7 of 6346 chromosomes (freq: 0.001), Latino in 48 of 33802 chromosomes (freq: 0.001), European in 20 of 123952 chromosomes (freq: 0.0002), Ashkenazi Jewish in 14 of 9952 chromosomes (freq: 0.001), and South Asian in 1 of 30008 chromosomes (freq: 0.00003); it was not observed in the East Asian, and Finnish populations. The p.Arg232 residue is conserved in mammals but not in more distantly related organisms however four out of five 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, HumanSpliceFinder) do not predict a difference in splicing. This variant was identified in an individual with HBOC and a co-occurring BRCA2 variant (c.6405_6409del) increasing the likelihood the RAD51D c.695G>A variant may not have clinical significance. 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.

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