ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2992_2995del (p.Lys998fs) (rs786203717)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167141 SCV000217971 pathogenic Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Deficient protein function in appropriate functional assay(s)
Invitae RCV000458808 SCV000547323 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2019-09-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRIP1 gene (p.Lys998Glufs*60). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 252 amino acids of the BRIP1 protein. This variant is not present in population databases (rs786203717, ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 18628483, 26921362, 28423363). ClinVar contains an entry for this variant (Variation ID: 187416). This variant disrupts the C-terminal 252 amino acid residues of the BRIP1 protein, partially disrupting the BRCA1-interacting domain that is essential for proper BRIP1 function (PMID: 21345144). It is also expected to disrupt the TopBP1-BRIP1 interaction that plays a critical role in RPA chromatin loading in response to DNA damage (PMID: 20159562, 21127055). Experimental studies have shown that this variant leads to the expression of a truncated, unstable protein that has impaired ability to bind to BRCA1 (PMID: 18628483). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000478533 SCV000564817 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRIP1 is denoted c.2992_2995delAAGA at the cDNA level and p.Lys998GlufsX60 (K998EfsX60) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AACA[delAAGA]GAGT. The deletion causes a frameshift, which changes a Lysine to a Glutamic Acid at codon 998, and creates a premature stop codon at position 60 of the new reading frame. It is predicted to cause loss of normal protein function through protein truncation as the last 252 correct amino acids are replaced by 59 incorrect ones, disrupting the BRCA1 binding domain (Cantor 2011). BRIP1 c.2992_2995delAAGA was reported in a woman with early-onset breast cancer whose tumor demonstrated loss of heterozygosity of the wild type allele as well as in 1/1,313 breast cancer cases in a case-control study (De Nicolo 2008, Thompson 2016). In addition, functional studies found that this variant impaired both protein stability and interaction with BRCA1 (De Nicolo 2008). We consider this variant to be pathogenic.
Color RCV000167141 SCV000684241 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-03 criteria provided, single submitter clinical testing
Counsyl RCV000663176 SCV000786341 pathogenic Fanconi anemia, complementation group J; Neoplasm of ovary 2018-04-13 criteria provided, single submitter clinical testing

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