ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.671-1G>C (rs80358020)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236539 SCV000293326 uncertain significance not provided 2015-11-09 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.671-1G>C or IVS9-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 9 of the BRCA1 gene. Using alternate nomenclature this variant would be defined as BRCA1 790-1G>C or IVS10-1G>C. This variant has not, to our knowledge, been published in the literature. BRCA1 c.671-1G>C destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing. However, the transcript predicted to result from this variant, an in-frame deletion of exon 10, is a splicing isoform noted to be present at low levels in normal breast tissue and peripheral blood lymphocytes from control individuals (Brandao 2011, Colombo 2014). Rosenthal et al. (2015) reported nearby BRCA1 variants predicted to impact splicing as being clinically insignificant based on a high frequency in control populations, co-occurrence with known pathogenic BRCA1/2 variants, and inconsistent segregation and phenotype data. One such variant, BRCA1 c.591C>T (p.Cys197Cys), was reported by Dosil et al. (2010) to induce exon 9 (now referred to as exon 8) skipping while simultaneously increasing expression of other naturally occurring splicing isoforms which preserve the open reading frame. Based on these findings, Rosenthal et al. (2015) proposed that alternative transcripts may rescue" variants that disrupt splicing for what are now defined as exons 8 and 9, and a similar phenomenon could occur with BRCA1 c.671-1G>C. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Despite this variant's predicted effect on splicing, based on currently available evidence we consider BRCA1 c.671-1G>C to be a variant of uncertain significance."
Sharing Clinical Reports Project (SCRP) RCV000077180 SCV000108977 uncertain significance Breast-ovarian cancer, familial 1 2012-08-31 no assertion criteria provided clinical testing

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