Submissions for variant NM_032043.3(BRIP1):c.2286T>C (p.Arg762=)

gnomAD frequency: 0.00173  dbSNP: rs61754141

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212321	SCV000167432	benign	not specified	2014-02-03	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.
Ambry Genetics	RCV000124023	SCV000213125	likely benign	Hereditary cancer-predisposing syndrome	2014-06-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001079356	SCV000252875	benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410265	SCV000404597	likely benign	Fanconi anemia complementation group J	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Counsyl	RCV000410265	SCV000489979	likely benign	Fanconi anemia complementation group J	2016-09-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000411328	SCV000489980	likely benign	Neoplasm of ovary	2016-09-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212321	SCV000593764	benign	not specified	2021-04-19	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000124023	SCV000679728	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000124023	SCV000684203	likely benign	Hereditary cancer-predisposing syndrome	2015-12-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586863	SCV000699688	benign	not provided	2016-03-07	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.2286T>C variant affects a conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts a damaging outcome for this variant. 3/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect ESE site of SF2/ASF (IgM-BRCA1). However, these predictions have not been confirmed by experimental studies. This variant is found in 61/121286 control chromosomes (1 homozygote) at a frequency of 0.0005029, which is about 8 times the maximal expected frequency of a pathogenic BRIP1 allele (0.0000625), suggesting this variant is benign. In addition, multiple clinical laboratories classified this variant as likely benign/benign. Taken together, this variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000212321	SCV000807132	benign	not specified	2017-08-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586863	SCV000889213	benign	not provided	2022-12-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586863	SCV002049891	benign	not provided	2020-10-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000124023	SCV002531406	benign	Hereditary cancer-predisposing syndrome	2020-08-25	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315839	SCV004019399	benign	Familial cancer of breast	2023-03-01	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
CeGaT Center for Human Genetics Tuebingen	RCV000586863	SCV004145817	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	BRIP1: BP4, BP7
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492565	SCV004240393	likely benign	Breast and/or ovarian cancer	2023-05-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358580	SCV001554361	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Arg762= variant was identified in 1 of 188 proband chromosomes (frequency: 0.005) from individuals or families with prostate cancer (Ray 2009). The variant was also identified in the following databases, dbSNP (ID: rs61754141) as “With Uncertain significance allele”, ClinVar (7x, as benign by GeneDx, Invitae, as likely benign by Ambry Genetics, Counsyl, as uncertain significance by Illumina), Clinvitae (6x, with conflicting predictions as benign, likely benign and uncertain significance), Zhejiang Colon Cancer Database (1x with unknown pathogenicity). The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 179 of 276976 (1 homozygous) chromosomes at a frequency of 0.0006 in the following populations: African in 129 of 24038 (1 homozygous) chromosomes (freq. 0.005), other in 2 of 6462 chromosomes (freq. 0.0003), Latino in 25 of 34400 chromosomes (freq. 0.0007), European in 22 of 126538 chromosomes (freq. 0.0002), and South Asian in 1 of 30782 chromosomes (freq. 0.00003), increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The p.Arg762Arg variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.