ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2990_2993delCAAA (rs771028677)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214087 SCV000278904 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRIP1 is denoted c.2990_2993delCAAA at the cDNA level and p.Thr997ArgfsX61 (T997RfsX61) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAAA[delCAAA]GAGA. The deletion causes a frameshift, which changes a Threonine to an Arginine at codon 997, and creates a premature stop codon at position 61 of the new reading frame. It is predicted to cause loss of normal protein function through protein truncation as the last 253 amino acid residues are replaced by 60 incorrect ones, disrupting the BRCA1 binding domain (Cantor 2011). This variant has been observed in individuals with personal and/or family history of breast or ovarian cancer and in an individual with colon cancer (Ramus 2015, Easton 2016, Thompson 2016, Yurgelun 2017). Additionally, a nearby variant resulting in a similar protein change, BRIP1 c.2992_2995delAAGA, was found to impair protein stability and BRCA1 interaction (De Nicolo 2008). Based on currently available evidence, we consider BRIP1 c.2990_2993delCAAA to be pathogenic.
Invitae RCV000230820 SCV000291027 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-23 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 20 of the BRIP1 mRNA (c.2990_2993delCAAA), causing a frameshift at codon 997. This creates a premature translational stop signal in the last exon of the BRIP1 mRNA (p.Thr997Argfs*61). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated BRIP1 protein. This variant is present in population databases (rs771028677, ExAC 0.003%). This variant has been reported in an individual with a family history of breast and ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 234281). This variant affects the C-terminal BRCA1-binding domain (residues 888-1063) of the BRIP1 protein, and therefore is expected to disrupt BRIP1-BRCA1 interaction (PMID: 21345144). Other variant that similarly disrupts this region (p.Lys998Glufs*60) have been determined to be pathogenic (PMID: 18628483, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Color RCV000234901 SCV000292145 pathogenic Hereditary cancer-predisposing syndrome 2015-03-05 criteria provided, single submitter clinical testing
Counsyl RCV000410664 SCV000490005 likely pathogenic Fanconi anemia, complementation group J 2016-09-20 criteria provided, single submitter clinical testing
Counsyl RCV000411728 SCV000490006 likely pathogenic Neoplasm of ovary 2016-09-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000234901 SCV000661461 pathogenic Hereditary cancer-predisposing syndrome 2018-04-02 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Mendelics RCV000410664 SCV000839357 pathogenic Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000214087 SCV001134021 pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.

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