ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8754+3G>C (rs397508007)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131319 SCV000186292 likely pathogenic Hereditary cancer-predisposing syndrome 2017-07-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Functionally-validated splicing mutation
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258465 SCV000327955 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000258465 SCV000744548 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000258465 SCV000733322 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
GeneDx RCV000521379 SCV000617475 likely pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8754+3G>C or IVS21+3G>C and consists of a G>C nucleotide substitution at the +3 position of intron 21 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 8982+3G>C. This variant has been observed in at least two families with breast and/or ovarian cancer (Brandao 2011, Thomassen 2012). BRCA2 c.8754+3G>C was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). The guanine (G) nucleotide that is altered is conserved in mammals. Multiple in silico models predict this variant to weaken the nearby natural donor site and to cause abnormal gene splicing. Multiple functional studies, including minigene splicing assays and RT-PCR mRNA analyses, have demonstrated that this variant induces retention of 46 nucleotides within the transcript, resulting in a predicted frameshift and truncated protein (Brandao 2011, Thomassen 2012, Colombo 2013). Based on the currently available information, we consider BRCA2 c.8754+3G>C to be a likely pathogenic variant.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000258465 SCV000743351 pathogenic Breast-ovarian cancer, familial 2 2014-10-08 criteria provided, single submitter clinical testing
Invitae RCV000045614 SCV000073627 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-18 criteria provided, single submitter clinical testing This sequence change falls in intron 21 of the BRCA2 mRNA. It does not directly change the encoded amino acid sequence of the BRCA2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families with hereditary breast and ovarian cancer (PMID: 21638052, 23451180, 21769658, 21520333). ClinVar contains an entry for this variant (Variation ID: 52668). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts splicing, leading to the inclusion of 46 nucleotides of intron 21, and causes a downstream frameshift and subsequent premature stop codon (PMID: 21638052, 23451180, 21769658). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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