Submissions for variant NM_032043.3(BRIP1):c.1315C>T (p.Arg439Ter)

gnomAD frequency: 0.00001  dbSNP: rs587780226

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116121	SCV000150030	pathogenic	not provided	2023-03-29	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 significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect: failed to confer resistance to inter-strand crosslink-inducing agents (Calvo et al., 2021); This variant is associated with the following publications: (PMID: 29922827, 26556299, 26296696, 26681312, 28495237, 28849200, 26921362, 26099045, 33151324, 35273153, 26845104, 33313162, 30982232, 30850667, 36627197, 33619228, 32566746, 35053526, 33842585)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210150	SCV000266056	pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210150	SCV000274380	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-25	criteria provided, single submitter	clinical testing	The p.R439* pathogenic mutation (also known as c.1315C>T), located in coding exon 8 of the BRIP1 gene, results from a C to T substitution at nucleotide position 1315. This changes the amino acid from an arginine to a stop codon within coding exon 8. In a functional study, this alteration was found to cause cisplatin sensitivity (Calvo JA et al. Mol Cancer Res, 2021 Feb;:). This mutation has been reported in 1/384 Chinese high-risk breast cancer patients (Lang GT et al. Ann Transl Med, 2020 Nov;8:1417), in two Ashkenazi Jewish women with personal and family history of breast cancer who underwent multigene panel testing (Frey MK et al. Gynecol Oncol, 2017 07;146:123-128), in a patient diagnosed with colorectal cancer at age 45 who underwent multigene panel testing (Shirts BH et al. Genet Med, 2016 10;18:974-81), in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet Med, 2016 08;18:823-32), and in 1/13213 breast cancer cases and 0/5242 controls from the UK (Easton DF et al. J Med Genet, 2016 05;53:298-309). 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.
Counsyl	RCV000662793	SCV000785606	pathogenic	Fanconi anemia complementation group J; Ovarian neoplasm	2017-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV000699261	SCV000827963	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.Arg439*) 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 (rs587780226, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312, 26845104). ClinVar contains an entry for this variant (Variation ID: 128154). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000210150	SCV001345203	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. In a high-throughput in vitro assay, this variant failed to restore resistance to interstrand crosslink (ICL) inducing agents (PMID: 33619228). This variant has been reported in individuals affected with breast, ovarian, colon, and gastric cancer (PMID: 26681312, 26845104, 33313162, 33842585, 36627197). This variant has been identified in 3/251156 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.
Myriad Genetics, Inc.	RCV003315646	SCV004019506	pathogenic	Familial cancer of breast	2023-03-02	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.
PreventionGenetics, part of Exact Sciences	RCV003483484	SCV004118998	pathogenic	BRIP1-related disorder	2023-03-15	criteria provided, single submitter	clinical testing	The BRIP1 c.1315C>T variant is predicted to result in premature protein termination (p.Arg439*). This variant has been reported in individuals with breast cancer (Frey et al. 2015. PubMed ID: 26296696; Easton et al. 2016. PubMed ID: 26921362. Table S1), Seminoma (Schrader et al. 2016. PubMed ID: 26556299. Table S8), as well as colorectal cancer (Shirts et al. 2016. PubMed ID: 26845104). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59876486-G-A) and interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128154/). Nonsense variants in BRIP1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003315646	SCV004217115	pathogenic	Familial cancer of breast	2024-03-24	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV001787088	SCV002029141	not provided	Familial ovarian cancer		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-09-2016 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Laboratory for Genotyping Development, RIKEN	RCV003162547	SCV002758230	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV003483484	SCV004228813	not provided	BRIP1-related disorder		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-09-2016 by Lab Myriad Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.