ClinVar Genomic variation as it relates to human health

This variant is a single base pair deletion from exon 20 of the BRIP1 mRNA, causing a frameshift after codon 983 and this creates a premature translational stop signal 2 amino acid residues later. This variant is expected to disrupt BRIP1-BRCA1 interaction because affects the BRCA1-binding domain (residues 888-1063) of the BRIP1 protein (PMID: 21345144). Truncating variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 461044).

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

This variant deletes 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift at codon 983 and premature translation stop signal at codon 984 in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the functional domains involved in BRCA1-binding, DNA damage and replication stress responses and attenuation of DNA damage tolerance pathway (PMID: 11301010, 14983014, 20159562, 20173781, 22792074). Although functional studies have not been reported for this variant, this variant is expected to impair important BRIP1 protein function. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250646 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.Ile983Leufs*2) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 267 amino acid(s) of the BRIP1 protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 461044). This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Thr997Argfs*61, p.Lys998Glufs*60, p.Lys998Glufs*3) have been determined to be pathogenic (PMID: 18628483; 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 p.Ile983LeufsX2 variant in BRIP1 Reported in 2 breast cancer patients (Siraj 2017 PMID: 28975465) and 1 pt with hereditary breast cancer (with a family history of breast cancer) (Lerner-Ellis 2021 PMID: 32885271).This variant is absent in large population databases gnomad chromosomes by gnomAD. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 983 and leads to a premature termination codon 2 amino acids downstream. This alteration is in the last exon and is expected to evade nonsense-mediated decay (NMD); however, the variant impacts a region of the protein critical to its function (Gong 2010 PMID: 20159562, Xie 2012 PMID: 22792074) and several downstream missense variant have been associated with predisposition to cancer. Loss of function of the BRIP1 gene is an established disease mechanism in autosomal dominant cancer predisposition syndrome and autosomal recessive fanconi anemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant cancer predisposition syndrome and for autosomal recessive fanconi anemia. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PS4_Supporting.

The c.2947delA pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 2947, causing a translational frameshift with a predicted alternate stop codon (p.I983Lfs*2). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 267 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration was detected in an individual diagnosed with breast cancer at age 46 who had a family history of breast cancer (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration was also seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Curator: Arleen D. Auerbach. Submitter to LOVD: Florentia Fostira.

The BRIP1 c.2947del variant was not identified in the literature nor was it identified in the dbSNP. The variant was identified ClinVar (classified pathogenic by Invitae and /likely pathogenic by GeneKor MSA). The variant was identified in control databases in 1 of 250646 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 113472 chromosomes (freq. 0.00001), while the variant was not observed in the African, Other, South Asian, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The c.2947del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 983 and leads to a premature stop codon at position 984. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRIP1 gene are an established mechanism of disease in BRIP1 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

Diagnosis: Breast Cancer Pathology: Invasive Ductal Ca IHC: ER:+, PR:+, HER2:-, Ecadherin:+ Ki67:%20