ClinVar Genomic variation as it relates to human health

Variant summary: BRIP1 c.2010dupT (p.Glu671X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.1e-05 in 261786 control chromosomes (gnomAD). c.2010dupT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Seal_2006, Ramus_2015, Easton_2016, Weber-Lasalle_2018) . These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The BRIP1 c.2010dup (p.Glu671Ter) change is a single nucleotide duplication that creates a premature stop codon and is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/17-59853848-C-CA?dataset=gnomad_r2_1). This variant has been observed in individuals with breast cancer (PMID: 17033622, 26921362), ovarian cancer (PMID: 26315354, 29368626, 30322717), and peritoneal cancer (PMID: 22006311). This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_supporting.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22006311, 17033622, 26315354, 26720728, 20346647, 19763819, 26921362, 30322717, 29368626, 30267214, 29922827, 31173646, 32359370, 21964575, 16116423, 28888541)

This variant inserts 1 nucleotide in exon 14 of the BRIP1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, ovarian, peritoneal, and colorectal cancer in the literature (PMID: 17033622, 22006311, 26315354, 26921362, 29368626, 30267214). This variant has been identified in 2/251302 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Glu671*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs775537066, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and peritoneal cancer (PMID: 17033622, 22006311, 26315354, 26921362). This variant is also known as 2008insT and 2010insT. ClinVar contains an entry for this variant (Variation ID: 187476). For these reasons, this variant has been classified as Pathogenic.

The c.2010dupT pathogenic mutation, located in coding exon 13 of the BRIP1 gene, results from a duplication of T at nucleotide position 2010, causing a translational frameshift with a predicted alternate stop codon (p.E671*). This alteration has been observed in individuals diagnosed with breast, ovarian, peritoneal and colorectal cancer (Seal S et al. Nat. Genet. 2006 Nov;38:1239-41; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:; Easton DF et al. J Med Genet, 2016 05;53:298-309; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806; Weber-Lassalle N et al. Breast Cancer Res. 2018 Jan;20(1):7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

The BRIP1 c.2010dup (p.Glu671*) variant causes the premature termination of BRIP1 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 17033622 (2006)), ovarian cancer (PMIDs: 30322717 (2018), 29368626 (2018), 26315354 (2015)), peritoneal cancer (PMID: 22006311 (2011)), and colorectal cancer (PMID: 30267214 (2018)). The frequency of this variant in the general population, 0.000008 (2/251302 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

The BRIP1 c.2010dupT variant is predicted to result in premature protein termination (p.Glu671*). This variant has been reported primarily in individuals with breast or ovarian cancer but has also been reported in individuals with colorectal, peritoneal, and lung cancer (see, for example, Seal et al. 2006. PubMed ID: 17033622; Supplementary Table 2, Ramus et al. 2015. PubMed ID: 26315354; Rosenthal et al. 2018. PubMed ID: 30267214; Table S2, Walsh et al. 2011. PubMed ID: 22006311; Table S6, Lee et al. 2023. PubMed ID: 37461096). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59853848-C-CA). It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187476/). Nonsense variants in BRIP1 are expected to be pathogenic. This variant is interpreted as pathogenic.