ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8755-19A>G (rs398122713)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122936 SCV000166194 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000160155 SCV000210481 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8755-19A>G or IVS21-19A>G and consists of a A>G nucleotide substitution at the -19 position of intron 21 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 8983-19A>G. Multiple in silico models predict that this variant results in the gain of a cryptic splice acceptor site upstream of the natural splice acceptor site, possibly leading to abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 c.8755-19A>G was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The adenine (A) nucleotide that is altered is not conserved. Based on currently available evidence, it is unclear whether BRCA2 c.8755-19A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV001199407 SCV000494403 likely benign not specified 2020-06-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8755-19A>G 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. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates an additional intronic 3' acceptor site before the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 249352 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8755-19A>G has been reported in the literature in at-least one affected proband with a family history of breast cancer (example, Torres_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=2). We have not ascertained any evidence supporting a pathogenic outcome for this variant in over five years since its initial observation at our laboratory. Based on the evidence outlined above, to reflect the emerging consensus interpretation among submitters in the field, the variant was re-classified as likely benign.
Counsyl RCV000077642 SCV000785049 likely benign Breast-ovarian cancer, familial 2 2018-06-13 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000160155 SCV000805784 uncertain significance not provided 2017-10-04 criteria provided, single submitter clinical testing
Color RCV000776372 SCV000911800 likely benign Hereditary cancer-predisposing syndrome 2017-06-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077642 SCV000109445 likely benign Breast-ovarian cancer, familial 2 2014-06-11 no assertion criteria provided clinical testing

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