ClinVar Genomic variation as it relates to human health

Variant summary: BRIP1 c.2992_2993delAA (p.Lys998GlufsX3) 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 2.3e-05 in 265460 control chromosomes (gnomAD and publications). c.2992_2993delAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Maxwell_2015, Lilyquist_2017, Nassar_2020), while it has also been reported in an unaffected individual with a family history of breast cancer (Mersch_2018) and in healthy controls (e.g. Easton_2016, Thompson_2016, FLOSSIES database). These data indicate that the variant may be associated with disease. A co-occurrence with another pathogenic variant has been reported in a breast cancer patient (BRCA1 c.68_69delAG, p.Glu23ValfsX17; Kadri_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Other frameshift variants in this region of the BRIP1 gene are cited in HGMD and ClinVar databases as disease-associated/pathogenic (e.g. c.2990_2993delCAAA, p.Thr997ArgfsX61; c.2992_2995delAAGA, p.Lys998GlufsX60). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This frameshift variant in exon 20 of 20 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has not been previously reported or functionally characterized in the literature to our knowledge. A different variant (c.2992_2995delAAGA, p.Lys998Glufs*60) that disrupts this region has been reported as pathogenic (PMID: 18628483, 26921362, 28423363, 30322717). The c.2992_2993delAA (p.Lys998GlufsTer3) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (1/250982) and thus is presumed to be rare. Based on the available evidence, the c.2992_2993delAA (p.Lys998GlufsTer3) variant is classified as Pathogenic.

Frameshift variant predicted to result in abnormal protein length as the last 252 amino acids are replaced with 2 different amino acids; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer, ovarian cancer, urothelial cancer, and also detected in unaffected controls (PMID: 26921362, 28888541, 31844177, 26786923, 25503501, 33552952); This variant is associated with the following publications: (PMID: 29922827, 30264118, 26786923, 26921362, 28888541, 31844177, 11301010, 21127055, 20159562, 18628483, 28423363, 32359370, 36260514, 25503501, 33552952)

This variant deletes 2 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last coding exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported for this variant, it is expected to disrupt functional domains involved in BRCA1-binding and DNA damage and replication stress response (PMID: 11301010, 14983014, 20159562, 20173781, 22792074). This variant has been reported in individuals affected with breast cancer and urothelial carcinoma (PMID: 25503501, 26921362, 31844177) and in unaffected individuals (PMID: 26786923, 30254378, 30264118). This variant has been identified in 1/250982 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 Likely Pathogenic.

This sequence change creates a premature translational stop signal (p.Lys998Glufs*3) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 252 amino acid(s) of the BRIP1 protein. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 241648). This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Lys998Glufs*6) have been determined to be pathogenic (PMID: 18628483, 26921362, 28423363; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The c.2992_2993delAA pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from a deletion of two nucleotides at nucleotide positions 2992 to 2993, causing a translational frameshift with a predicted alternate stop codon (p.K998Efs*3). 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 impacts the last 252 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

This frameshift variant alters the translational reading frame of the BRIP1 mRNA and causes the premature termination of BRIP1 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/250982 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with ovarian cancer (PMID: 28888541 (2017)), breast cancer (PMID: 25503501 (2015), 26921362 (2016), 31844177 (2020), 33552952 (2020)), and bladder cancer (25503501 (2015), 31844177 (2020)). Based on the available information, this variant is classified as pathogenic.

The p.Lys998GlufsX3 variant in BRIP1 has been reported in 1 individual from an ovarian cancer cohort (Lilyquist 2017 PMID: 28888541) and was absent in large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 998 and leads to a premature termination codon 3 amino acids downstream. The variant occurs in the last exon and may escape mRNA nonsense mediated decay; however it's predicted to remove ~20% of the protein impacting the c-terminus region which is critical for protein function (Leung 2011 PMID: 21127055, Gong 2010 PMID: 20159562). Other frameshift variants at the same codon (c.2992_2995delAAGA, p.Lys998Glufs*60) or downstream of this variant has been reported in individuals with ovarian breast cancer. Loss of function of BRIP1 is an established disease mechanism for autosomal dominant ovarian cancer and autosomal recessive Fanconi anemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ovarian cancer and autosomal recessive Fanconi anemia. ACMG/AMP criteria applied: PVS1_Strong, PM1, PM2_Supporting.