ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8487+8G>A (rs81002838)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083705 SCV000073550 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-23 criteria provided, single submitter clinical testing
GeneDx RCV000045537 SCV000210670 benign not specified 2014-08-19 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 RCV000031746 SCV000220472 likely benign Breast-ovarian cancer, familial 2 2014-07-02 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000195336 SCV000600808 likely benign not provided 2019-03-11 criteria provided, single submitter clinical testing
Color Health, Inc RCV000581089 SCV000683970 likely benign Hereditary cancer-predisposing syndrome 2016-07-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045537 SCV000695157 likely benign not specified 2019-01-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8487+8G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing, which is supported by a functional study (Whiley 2011). The variant allele was found at a frequency of 5e-05 in 282452 control chromosomes, predominantly within the African subpopulation at a frequency of 0.00048 in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00048 vs 0.00075), allowing no conclusion about variant significance. c.8487+8G>A has been reported in the literature in individuals affected with breast and cancer or other tumor phenotypes (Haffty 2009, Whiley 2011), however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A statistical variant reclassification tool based on a personal and family history weighting algorithm predicted that the variant belongs to the benign spectrum (Pruss 2014). Co-occurrence with another pathogenic variant has been reported (BRCA1 c.4986+6T>C; in an internal sample), providing supporting evidence for a benign role. No additional evidence supporting pathogenicity has been identified since its previous evaluations spanning a three year time frame at our laboratory. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000031746 SCV001139216 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031746 SCV000054353 likely benign Breast-ovarian cancer, familial 2 2011-07-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031746 SCV000147381 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353581 SCV000592197 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The c.8487+8G>A variant was not identified in the literature, but was identified in dbSNP (ID: rs81002838), the BIC database (1X with unknown clinical importance), the UMD (1X as an unclassified variant), and the ClinVar database (classified as likely benign by the Sharing Clinical Reports Project (derived from Myriad reports)).The variant was identified by the Exome Variant Server project in 2 of 4406 African American alleles (frequency: 0.0005) and in the 1000 Genomes Project in 1 allele (frequency 0.0005), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The c.8487+8G>A 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. However, this information is not predictive enough to rule out pathogenicity. 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 unknown significance.

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