ClinVar

Description

The BRIP1 p.Arg798X variant was identified in 31 of 118976 proband chromosomes (frequency: 0.0003) from families with high risk BRCA1/2/PALB2 negative breast cancer, early-onset or familial breast cancer, ovarian cancer, Lynch syndrome, prostate cancer, or triple negative breast cancer and was identified in 3 of 102538 control chromosomes from healthy individuals (frequency: 0.00003, Lhota 2016, McInerney 2010, Seal 2006, Yurgelun 2015, Kote-Jarai 2009, Leongamornlert 2014, Ramus 2015, Couch 2015). Segregation studies in 1 proband with prostate cancer showed partial segregation of the variant with disease, with 1 affected sibling carrying the variant and the other affected sibling testing negative (Kote-Jarai 2009). Analysis of the variant protein, from lymphoblastoid cell lines, by immunoblotting showed an absence of the protein in both homozygous and heterozygous carriers and absence of homologous recombination (Levran 2005, Litman 2005). cDNA sequencing of 1 proband with Fanconi anemia carrying the variant with a co-occurring BRIP1 variant (IVS17+2insT), identified 3 mRNA transcripts, 2 lacking either exon 17 or 18 and both leading to a frameshift yielding a partial deletion of the helicase motif and BRCA1 binding site (Levitus 2005). The variant was also identified in dbSNP (ID: rs137852986) as “With Pathogenic allele”, ClinVar (with conflicting interpretations of pathogenicity; submitters: pathogenic by GeneDx, Ambry Genetics, Invitae, and 5 additional submitter, as Likely pathogenic by Counsyl, and uncertain significance by Illumina), Cosmic (1x in carcinoma of salivary gland), Zhejiang University Database (20x) and was not identified in MutDB. The variant was identified in control databases in 45 of 273100 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). It was observed in the European Non-Finnish population in 35 of 125106 chromosomes (freq: 0.0003), the African population in 1 of 23852 chromosomes (freq: 0.00004), “Other” in 2 of 6376 chromosomes (freq: 0.0003), Latino in 4 of 33846 chromosomes (freq: 0.0001), East Asian in 1 of 18232 chromosomes (freq: 0.00006), and South Asian in 2 of 30042 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish, and Finnish populations. The c.2392C>T variant is predicted to lead to a premature stop codon at amino acid position 798 which is predicted to lead to 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 cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant is classified as pathogenic.