Submissions for variant NM_032043.3(BRIP1):c.3196del (p.Ser1066fs)

gnomAD frequency: 0.00006  dbSNP: rs730881645

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590317	SCV000210864	likely pathogenic	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 184 amino acids are lost and replaced with11 incorrect amino acids; Observed in individuals with breast and other cancers (Tung et al., 2015; Huang et al., 2018; Zheng et al., 2018; Slavin et al., 2019; George et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29625052, 25186627, 29922827, 30728895, 20159562, 21127055, 30130155, 33646313, 26689913, 34949788, 36451132, 35969835)
Ambry Genetics	RCV000220516	SCV000276797	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-31	criteria provided, single submitter	clinical testing	The c.3196delT variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of one nucleotide at position 3196, causing a translational frameshift with a predicted alternate stop codon (p.S1066Hfs*12). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and removes the last 173 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for the protein function (Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301. Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786; Gong Z et al. Mol. Cell. 2010 Feb;37:438-46). In addition, this alteration was identified in two studies in patients diagnosed with breast cancer younger than 50 years of age (Tung N et al. Cancer. 2015 Jan;121(1):25-33; Slavin TP et al. Oncotarget. 2019 Jan;10(4):417-423). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000460746	SCV000547269	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1066Hisfs*12) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 184 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs730881645, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with breast cancer, lung cancer (PMID: 25186627, 26689913, 30130155, 30728895, 33646313). 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000993845	SCV000699716	likely pathogenic	Hereditary breast ovarian cancer syndrome	2021-05-29	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 (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.
Color Diagnostics, LLC DBA Color Health	RCV000220516	SCV001339560	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift and a premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. This mutant protein would lack the region (codons 1130-1153) that has been shown to be important for TopBP1 binding in vitro and DNA replication-stress response in ex vivo cell culture (PMID: 20159562, 21127055). This variant has been reported in individuals of African ancestry affected with breast cancer (PMID: 25186627, 30130155, 30728895) and in an individual with endometrial cancer (PMID: 26689913, 28452373) in the literature, as well as in additional affected individuals tested by external laboratories (ClinVar variation ID: 182367). This variant has also been identified in 7/282816 chromosomes (7/24958 African chromosomes) in the general population by the Genome Aggregation Database (gnomAD) and in individuals lacking personal history of cancer (Color internal data; FLOSSIES, https://whi.color.com/). Based on the suspected deleterious impact on protein function and observations in affected individuals, this variant is classified as Likely Pathogenic. The occurrence of this variant in the general population (gnomAD) and in some unaffected individuals suggest this variant may show reduced penetrance compared to other pathogenic variants in the BRIP1 gene.
Baylor Genetics	RCV003462085	SCV004217116	likely pathogenic	Familial cancer of breast	2023-05-18	criteria provided, single submitter	clinical testing