ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.1343G>A (p.Trp448Ter)

gnomAD frequency: 0.00002  dbSNP: rs775171520
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000198848 SCV000253958 pathogenic Familial cancer of breast; Fanconi anemia complementation group J 2023-11-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp448*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs775171520, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with a personal or familial history of breast cancer (PMID: 26824983). ClinVar contains an entry for this variant (Variation ID: 216129). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000449028 SCV000537648 pathogenic Hereditary cancer-predisposing syndrome 2023-06-13 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 10 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 26824983, 31742824, 33649982) and colorectal cancer (PMID: 31118792) in the literature. This variant has been identified in 6/246588 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 Pathogenic.
Ambry Genetics RCV000449028 SCV000661582 pathogenic Hereditary cancer-predisposing syndrome 2024-10-08 criteria provided, single submitter clinical testing The p.W448* pathogenic mutation (also known as c.1343G>A), located in coding exon 9 of the BRIP1 gene, results from a G to A substitution at nucleotide position 1343. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. In one study, this alteration was classified as a loss of function mutation based on its failure to confer resistance to either cisplatin or mitomycin C treatment (Calvo JA et al. Mol Cancer Res, 2021 Jun;19:1015-1025). In addition, this alteration has been reported in one individual from an Asian-Pacific cohort of 133 breast cancer patients with early onset or bilateral breast cancer or with a family history of breast and/or ovarian cancer (Lin PH et al. Oncotarget 2016 Feb;7:8310-20). This alteration was also reported in two individuals with personal history of bladder and colon cancer, respectively, from a cohort of 1191 cancer index patients who underwent clinical evaluation and testing with multigene panels (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660), and in 1/618 unselected Chinese colorectal cancer patients (Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586228 SCV000699662 likely pathogenic Hereditary breast ovarian cancer syndrome 2015-11-27 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003335194 SCV004044599 pathogenic Familial cancer of breast 2023-06-01 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics RCV003335194 SCV004211356 pathogenic Familial cancer of breast 2024-02-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003477666 SCV004220682 pathogenic not provided 2022-12-22 criteria provided, single submitter clinical testing This nonsense variant causes the premature termination of BRIP1 protein synthesis. The frequency of this variant in the general population, 0.00033 (6/18306 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), 31742824 (2020), 26824983 (2016)), colorectal cancer (PMID: 31118792 (2019)), and bladder cancer (PMID: 30093976 (2018)). Based on the available information, this variant is classified as pathogenic.

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