ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7463G>A (p.Arg2488Lys) (rs80358968)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000168600 SCV000210650 likely benign not specified 2017-11-16 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.
Counsyl RCV000077401 SCV000488203 uncertain significance Breast-ovarian cancer, familial 2 2016-01-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000077401 SCV000575726 uncertain significance Breast-ovarian cancer, familial 2 2015-08-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563199 SCV000661177 likely benign Hereditary cancer-predisposing syndrome 2018-07-23 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
Color Health, Inc RCV000563199 SCV000689049 likely benign Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168600 SCV000695069 likely benign not specified 2020-10-19 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7463G>A (p.Arg2488Lys) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7463G>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer and acute lymphoblastic leukemia (Claes_2004, Caux-Moncoutier_2009, de Smith_2019). Claes_2004 indicated the variant did not segregate with disease for one of the affected families. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, co-occurrences with other pathogenic variants have been reported (BRCA2 c.2745_2746delTT , p.Val917LysfsX18; BRCA1 c.1961dup, p.Tyr655ValfsX18; BRCA1 c.4183C>T, p.Gln1395X; BRCA1 c.IVS21+1G>T , c.5332+1G>T; BRCA1 c.4389C>A , p.Tyr1463X ; BRCA1 442_4357del , p.Glu149TyrfsX2, in UMD database), providing supporting evidence for a benign role. Although the variant is not located in a commonly known location to affect splicing (ie, within +/- 2 bp of an exon/intron junction), two publications found the variant to not affect splicing via functional studies (Caux-Moncoutier_2009, Houdayer_2012). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as likely benign.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077401 SCV000744518 uncertain significance Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Mendelics RCV000077401 SCV001139180 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284108 SCV001469714 uncertain significance not provided 2020-02-13 criteria provided, single submitter clinical testing
Invitae RCV001410830 SCV001612882 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-06 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077401 SCV000109198 likely benign Breast-ovarian cancer, familial 2 2012-11-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077401 SCV000147095 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001284108 SCV001550347 likely benign not provided no assertion criteria provided clinical testing BRCA2, EXON15, c.7463G>A, p.Arg2488Lys, Heterozygous, Likely BenignrnThe BRCA2 p.Arg2488Lys variant was identified in 3 of 7698 proband chromosomes (frequency: 0.0004) from individuals or families with breast or ovarian cancer (Claes 2004, Caux-Moncoutier 2009). The variant was also identified in dbSNP (ID: rs80358968) as "With other allele", ClinVar (classified as likely benign by GeneDx, Ambry Genetics, SCRP, Color and Integrated Genetics/Laboratory Corporation of America; and as uncertain significance by four submitters), LOVD 3.0 (14x), and UMD-LSDB (1x as neutral). In the UMD-LSDB database, the variant was identified in multiple cases as co-occurring with pathogenic BRCA1 variants (c.1961dup, p.Tyr655ValfsX18; c.4183C>T, p.Gln1395X; c.IVS21+1G>T, r.spl?; c.4389C>A, p.Tyr1463X; and c.442_4357del, p.Glu149TyrfsX2) and a pathogenic BRCA2 variant (c.2745_2746delTT, p.Val917LysfsX18), increasing the likelihood that the p.Arg2488Lys variant does not have clinical significance. The variant was identified in control databases in 3 of 246180 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33578 chromosomes (freq: 0.00003), European in 2 of 111652 chromosomes (freq: 0.00002), but not in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg2488 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. The literature suggests a neutral classification of the variant. Caux-Moncoutier (2009) used an allelic imbalance assay to assess the putative impact of variants on splicing; no allelic imbalance was found for the variant, suggesting that it does not impact splicing. In addition, Claes (2004) found that the variant did not segregate with disease in one family. In addition, several in silico and in vitro studies using PAXgene, Minigene systems or functional evidence identified no change and classified the variant neutral with no effect on splicing (Houdayer 2012, Martelotto 2014). 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.rnAssessment Date: 2019/07/22rnReferences (PMIDs): 15026808, 19471317, 22505045, 25348012, 19043619

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.