ClinVar

Description

Variant summary: BRIP1 c.3196delT (p.Ser1066HisfsX12) results in a premature termination codon in the last exon of the encoded mRNA, therefore it is not expected to result in nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein. No truncations downstream of this position were classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.5e-05 in 282816 control chromosomes, exclusively observed within the African or African-American subpopulation, at a frequency of 0.00028 (i.e. 7/24958 alleles) in the gnomAD database. In addition, this variant has also been reported in 1/2559 African American woman who was older than age 70 and cancer free (in the FLOSSIES database). c.3196delT has been reported in the literature in individuals of African ancestry, who were affected with breast cancer (example, Tung_2014, Zheng_2018, Slavin_2019). However, large-scale meta-analyses found that although BRIP1 mutations may confer risk for familial ovarian cancer, but not associated with increased risk for familial breast cancer (Weber-Lassale_2018, Suszynska_2018); therefore these reports do not allow any conclusions about variant significance. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.213-11T>G). Co-occurring pathogenic variants in different genes have been reported in cancer cases, thus this is not considered to weight as evidence supporting a benign impact of this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported for this variant. Though this truncation does not affect any known domains, in vitro studies have implicated a functional role for the region downstream of this variant in RPA phosphorylation in response to replication stress (i.e. following treatment with some DNA damaging agents) (example, Gong_2010, Xie_2012), however the contribution of these functional effects to the disease pathology remains uncertain. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and four of them classified the variant as likely pathogenic, while one reports a VUS classification. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on reports of its presence in patients with breast cancer (example, Zheng_2018, Slavin_2019), until additional clinical and functional evidence becomes available, the variant was classified as likely pathogenic.