Submissions for variant NM_032043.3(BRIP1):c.790C>T (p.Arg264Trp)

gnomAD frequency: 0.00104  dbSNP: rs28997569

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120409	SCV000150073	likely benign	not specified	2017-12-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001082519	SCV000166689	benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116164	SCV000183754	likely benign	Hereditary cancer-predisposing syndrome	2018-12-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV000120409	SCV000246815	likely benign	not specified	2015-08-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000411226	SCV000489857	likely benign	Fanconi anemia complementation group J	2016-07-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000409223	SCV000489858	likely benign	Ovarian neoplasm	2016-07-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116164	SCV000537408	likely benign	Hereditary cancer-predisposing syndrome	2015-01-22	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000515771	SCV000611880	likely benign	Familial cancer of breast	2018-03-28	criteria provided, single submitter	research	The BRIP1 variant designated as NM_032043.2:c.790C>T (p.Arg264Trp) is now classified as likely benign. The variant is present in approximately 1 in 500 individuals in European and African populations (exac.broadinstitute.org). This population frequency is not consistent with a high-risk cancer variant. In addition, there are no reports of pathogenic missense variants in this BRIP1 protein domain. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 128195). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BRIP1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
PreventionGenetics, part of Exact Sciences	RCV004528813	SCV000807157	likely benign	BRIP1-related disorder	2023-03-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679792	SCV000889226	likely benign	not provided	2021-02-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000515771	SCV001140786	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000411226	SCV001284961	uncertain significance	Fanconi anemia complementation group J	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679792	SCV001477824	likely benign	not provided	2023-10-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679792	SCV001501678	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	BRIP1: BP1
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000679792	SCV002010848	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798362	SCV002043641	likely benign	Breast and/or ovarian cancer	2023-06-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116164	SCV002529235	likely benign	Hereditary cancer-predisposing syndrome	2021-01-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120409	SCV002551199	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000515771	SCV004016917	likely benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000515771	SCV004019480	uncertain significance	Familial cancer of breast	2023-03-02	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
ITMI	RCV000120409	SCV000084561	not provided	not specified	2013-09-19	no assertion provided	reference population
Center of Medical Genetics and Primary Health Care	RCV001269494	SCV001449150	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001269494	SCV001549885	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Arg264Trp variant was identified in 55 of 46810 proband chromosomes (frequency: 0.001) from Italian, American, British and Colombian individuals or families with a wide spectrum of cancers (in population based studies, unselected for family history): BRCA1/2 negative, male/female breast cancer, prostate cancer, ovarian cancer, Lynch syndrome associated cancer and/or polyps, CRC, pancreatic cancer, hereditary prostate cancer and Fanconi anemia; and was present in 44 of 29724 control chromosomes (frequency: 0.001) from healthy individuals (Silvestri_2011_21165771, Bodian_2014_24728327, Hu_2016_26483394, Yurgelun_2015_25980754, Tung_20016_26976419, Seal_2006_17033622, Easton_2016_26921362, Levitus_2005_16116423, Pearlman_2016_27978560, Ramus_2015_26315354, Cock-Rada_2017_28528518, Ray_2009_19935797). In one prostate cancer family, the variant was identified in two out of three cases and was not present in the unaffected brother of the proband (Ray_2009_19935797). In 1 male proband with breast cancer, diagnosed at 76 yrs of age, DNA extracted from the micro-dissected breast tumor sample showed that no loss of the wild-type allele had occurred in tumor cells (Silvestri_2011_21165771). The variant was identified in dbSNP (ID: rs28997569) “With Likely benign allele”, ClinVar (classified likely benign by Invitae, Ambry Genetics, Genetic Services Laboratory (University of Washington), Counsyl, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, and GeneDx, and classification not provided by ITMI), Clinvitae (5x) and Zhejiang Colon Cancer Database, and was not identified in Cosmic or MutDB. The variant was also identified in control databases in 229 of 276746 chromosomes at a frequency of 0.0008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 17 of 24030 chromosomes (freq: 0.0007), “Other” in 11 of 6452 chromosomes (freq: 0.002), Latino in 15 of 34408 chromosomes (freq: 0.0004), European Non-Finnish in 145 of 126288 chromosomes (freq: 0.001), Ashkenazi Jewish in 28 of 10142 chromosomes (freq: 0.003), European Finnish in 7 of 25786 chromosomes (freq: 0.0003), and South Asian in 6 of 30782 chromosomes (freq: 0.0002); it was not observed in the East Asian population. The p.Arg264 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.