Submissions for variant NM_032043.3(BRIP1):c.2990_2993del (p.Thr997fs)

dbSNP: rs771028677

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214087	SCV000278904	pathogenic	not provided	2023-09-17	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 253 amino acids are replaced with 60 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Disrupts a critical functional domain: BRCA1 binding domain and TOPBP1 interaction domain (Cantor et al., 2001; Gong et al., 2010; Leung et al., 2011); This variant is associated with the following publications: (PMID: 26786923, 30675318, 26315354, 26921362, 18628483, 29478780, 28135145, 31214711, 32963463, 29922827, 28888541, 32885271, 34697415, 33804961, 11301010, 20159562, 21127055, MilanoL2023[preprint], 34308104, 35273153, 35753512, 29368626, 30254378, 32676327, 32191290, 34887416)
Invitae	RCV000230820	SCV000291027	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr997Argfs*61) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 253 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs771028677, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with a family history of breast and ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 234281). This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Lys998Glufs*60) have been determined to be pathogenic (PMID: 18628483; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000234901	SCV000292145	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the functional domains involved in BRCA1-binding, DNA damage and replication stress responses and attenuation of DNA damage tolerance pathway (PMID: 11301010, 14983014, 20159562, 20173781, 22792074). Although functional studies have not been reported for this variant, it is expected to impair BRIP1 protein function. This variant has been reported in individuals affected with breast cancer (PMID: 26921362, 36551643; Ma et al, 2019; Color Health internal data), in an individual with family history of breast and ovarian cancer (PMID: 26315354; Color Health internal data), in individuals affected with colorectal cancer (PMID: 28135145, 29478780, 30675318), in an individual affected with pancreatic cancer (PMID: 32885271), in an individual affected with prostate cancer (PMID: 31214711), and in individuals unaffected with breast cancer (PMID: 26921362, 30254378). This variant has been identified in 8/250982 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 Likely Pathogenic.
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	2021-04-05	criteria provided, single submitter	clinical testing	The c.2990_2993delCAAA pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from a deletion of four nucleotides between nucleotide positions 2990 and 2993, causing a translational frameshift with a predicted alternate stop codon (p.T997Rfs*61). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 253 amino acids of the protein. Premature stop codons are typically deleterious in nature and the C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for the protein function (Gong Z et al. Mol. Cell, 2010 Feb;37:438-46; Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301; Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786). This deletion has been identified in patients with a personal or family history of breast and/or ovarian cancer (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107; Easton DF et al. J Med Genet, 2016 05;53:298-309; Thompson ER et al. J Clin Oncol, 2016 May;34:1455-9) and has also been identified in controls or healthy individuals (Easton DF et al. J Med Genet, 2016 05;53:298-309; Thompson ER et al. J Clin Oncol, 2016 May;34:1455-9; Rowley SM et al. Genet Med, 2019 04;21:913-922). This variant has also been reported in a Japanese patient with prostate cancer (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376), a Han Chinese patient with gastric adenocarcinoma (Ji K et al. Chin J Cancer Res, 2020 Aug;32:508-515), a patient with pancreatic cancer (Hu C et al. JAMA, 2018 06;319:2401-2409), and in individuals affected with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095; AlDubayan SH et al. Am J Hum Genet, 2018 03;102:401-414). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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	2023-09-16	criteria provided, single submitter	clinical testing	The BRIP1 c.2990_2993del (p.Thr997Argfs*61) variant alters the translational reading frame of the BRIP1 mRNA and causes the premature termination of BRIP1 protein synthesis. This variant has been reported in the published literature in individuals with ovarian cancer (PMID: 26315354 (2015)), breast cancer (PMID: 26786923 (2016), 26921362 (2016), 36551643 (2022)), colorectal cancer (PMID: 28135145 (2017), 29478780 (2018)), pancreatic cancer (PMID: 29922827 (2018), 32885271 (2021)), a Lynch syndrome-associated cancer (PMID: 30254378 (2019)), prostate cancer (PMID: 31214711 (2020)), and gastric adenocarcinoma (PMID: 32963463 (2020)). This variant is also reported in unaffected individuals (PMID: 26786923 (2016), 26921362 (2016), 30254378 (2019)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193526	SCV001362421	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-24	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2990_2993delCAAA (p.Thr997ArgfsX61) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.9e-05 in 254976 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome (3.9e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.2990_2993delCAAA has been reported in the literature in individuals affected with Breast and Ovarian, Pancreatic and Prostate Cancer (Thompson 2016, Ramus 2015, Easton 2016, Lerner-Ellis_2021, Nguyen-Dumont_2021). These data indicate that the variant is very likely to be associated with disease. 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000234901	SCV001448945	pathogenic	Hereditary cancer-predisposing syndrome	2019-06-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000410664	SCV002017976	pathogenic	Fanconi anemia complementation group J	2023-12-06	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000214087	SCV002051718	pathogenic	not provided	2021-01-26	criteria provided, single submitter	clinical testing	PVS1, PS4_Moderate, PM2
Sema4, Sema4	RCV000234901	SCV002533665	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-02-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000214087	SCV002551155	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272183	SCV002556679	likely pathogenic	Familial cancer of breast	2020-11-24	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002272183	SCV002581719	likely pathogenic	Familial cancer of breast	2022-08-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002272183	SCV003928005	pathogenic	Familial cancer of breast	2023-06-01	criteria provided, single submitter	clinical testing	A known pathogenic mutation was detected in the BRIPI gene (c.2990_2993delCAAA).This sequence change creates a premature translational stop signal (p.Thr997Argfs*61) in the BRIPI gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 253 amino acid(s) of the BRIPI protein. This variant is present in population databases (rs771028677, gnomAD 0.006%). It has been reported in the literature in individuals affected with Breast and Ovarian, Pancreatic and Prostate Cancer (Thompson 2016, Ramus 2015, Easton 2016, Lerner-ElIis_202I, Nguyen-Dumont_2021). ClinVar contains an entry for this variant (Variation ID: 234281). This variant disrupts a region of the BRIPI protein in which other variant(s) (p.Lys998Glufs*60) have been determined to be pathogenic (PMID: 18628483). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be diseasecausing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV002272183	SCV004019296	pathogenic	Familial cancer of breast	2023-02-27	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV002272183	SCV004214670	pathogenic	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000214087	SCV004224960	likely pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	PS4_moderate, PVS1
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000214087	SCV001799364	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000214087	SCV001959010	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV003155936	SCV002588954	pathogenic	Ovarian cancer	2022-08-26	no assertion criteria provided	clinical testing