Submissions for variant NM_032043.3(BRIP1):c.133G>T (p.Glu45Ter)

dbSNP: rs587781292

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128992	SCV000172885	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	clinical testing	The p.E45* pathogenic mutation (also known as c.133G>T), located in coding exon 2 of the BRIP1 gene, results from a G to T substitution at nucleotide position 133. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196974	SCV000253957	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu45*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hereditary cancer (PMID: 24763289). ClinVar contains an entry for this variant (Variation ID: 140808). 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.
GeneDx	RCV000482088	SCV000568502	pathogenic	not provided	2021-10-18	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Laduca 2014, Ramus 2015); This variant is associated with the following publications: (PMID: 24763289, 26315354, 26921362, 29625052, 32885271)
Counsyl	RCV000662599	SCV000785234	pathogenic	Fanconi anemia complementation group J; Ovarian neoplasm	2017-06-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000196974	SCV000893466	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128992	SCV001735049	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 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 an individual affected with ovarian cancer (PMID: 26315354) and an individual/family suspected to be affected with hereditary breast and ovarian cancer (PMID: 24763289). This variant also has been detected in a breast cancer case-control meta-analysis in 2/53461 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000746). This variant has also been identified in 2/282808 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798433	SCV002043621	likely pathogenic	Breast and/or ovarian cancer	2021-08-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315866	SCV004019428	pathogenic	Familial cancer of breast	2023-03-01	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	RCV003315866	SCV004211332	pathogenic	Familial cancer of breast	2023-12-24	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000482088	SCV001549958	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRIP1 p.Glu45* variant was identified in 2 of 10630 proband chromosomes (frequency: 0.0002) from individuals or families with hereditary breast and ovarian cancer and was not identified in 6862 control chromosomes from healthy individuals (LaDuca 2014, Ramus 2015). The variant was also identified in dbSNP (ID: rs587781292) as "Pathogenic", ClinVar (as pathogenic by Ambry Genetics, Invitae, and GeneDx), and Cosmic databases. The variant was not identified in the MutDB and Zhejiang Colon Cancer Database. The variant was identified in control databases in 1 of 30980 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017), in the European population in 1 of 15010 chromosomes (freq: 0.00007); but not in in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, o South Asian populations. The p.Glu45* variant leads to a premature stop codon at position 45 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 hereditary breast and ovarian cancer 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.