ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3196del (p.Ser1066fs) (rs730881645)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590317 SCV000210864 likely pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3196delT at the cDNA level and p.Ser1066HisfsX12 (S1066HfsX12) at the protein level. The normal sequence, with the base that is deleted in brackets, is TGGA[delT]CATG. This variant causes a frameshift, which changes a Serine to a Histidine at codon 1066, and creates a premature stop codon at position 12 of the new reading frame. BRIP1 c.3196delT has been observed in at least one individual with early-onset breast cancer (Tung 2015). This variant is predicted to cause loss of normal protein function through protein truncation as the last 184 amino acids are lost and replaced with 11 incorrect amino acids. The disrupted region at the end of the gene is located within the TopBP1-binding region (Gong 2010). Based on currently available evidence, we consider BRIP1 c.3196delT to be likely pathogenic.
Ambry Genetics RCV000220516 SCV000276797 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-31 criteria provided, single submitter clinical testing Other strong data supporting pathogenic classification;Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Other data supporting pathogenic classification
Invitae RCV000460746 SCV000547269 likely pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2019-01-02 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 20 of the BRIP1 mRNA (c.3196delT), causing a frameshift at codon 1066. This creates a premature translational stop signal in the last exon of the BRIP1 mRNA (p.Ser1066Hisfs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated BRIP1 protein by eliminating the last 173 amino acids. This variant is present in population databases (rs730881645, ExAC 0.05%). This variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 182367). This truncation affects the TopBP1-binding region (residues 1130-1153) of the BRIP1 protein. It is expected to disrupt the TopBP1-BRIP1 interaction that plays a critical role on RPA chromatin loading following DNA replication stress and the subsequent activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). 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.
Counsyl RCV000576714 SCV000677806 likely pathogenic Fanconi anemia, complementation group J; Neoplasm of ovary 2017-06-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000993845 SCV000699716 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-21 criteria provided, single submitter clinical testing 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 (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 reported 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as likely pathogenic. Based on two additional reports of its presence in patients with breast cancer (Zheng_2018, Slavin_2019) since its initial assessment by our laboratory, until additional clinical and functional evidence becomes available, the variant was re-classified as likely pathogenic.

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