ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.68-1G>T (rs1060502376)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000775799 SCV000910252 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000458301 SCV000591658 pathogenic Hereditary breast and ovarian cancer syndrome 2015-06-29 criteria provided, single submitter clinical testing
GeneDx RCV000483572 SCV000569905 uncertain significance not provided 2016-04-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.68-1G>T or IVS2-1G>T and consists of a G>T nucleotide substitution at the -1 position of intron 2 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 296-1G>T. This particular variant has not, to our knowledge, been published in the literature. Although this variant destroys a canonical splice acceptor site and is predicted to cause abnormal splicing of exon 3, the skipping of exon 3 is predicted to be an in-frame event. Since the rest of the protein is expected to be translated, the loss of this one exon with no crucial functional domains has unclear clinical significance. Furthermore, a naturally occurring transcript of BRCA2 that lacks exon 3 has been reported in normal tissues and controls (Diez 2007, Muller 2011). In the absence of RNA or functional studies, the actual effect of this variant is unknown. We consider BRCA2 c.68-1G>T to be a variant of uncertain significance.
Invitae RCV000458301 SCV000549480 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 of the BRCA2 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with a BRCA2-related disease. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in BRCA2 are known to be pathogenic (PMID: 20104584). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.

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