Submissions for variant NM_032043.3(BRIP1):c.577G>A (p.Val193Ile)

gnomAD frequency: 0.00305  dbSNP: rs4988346

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120406	SCV000150070	benign	not specified	2017-05-14	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084461	SCV000153857	benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116161	SCV000185903	benign	Hereditary cancer-predisposing syndrome	2014-08-04	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
PreventionGenetics, part of Exact Sciences	RCV000120406	SCV000314843	benign	not specified		criteria provided, single submitter	clinical testing
Counsyl	RCV000410926	SCV000489805	benign	Fanconi anemia complementation group J	2016-05-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000412457	SCV000489806	benign	Ovarian neoplasm	2016-05-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120406	SCV000889220	benign	not specified	2021-08-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116161	SCV000902553	benign	Hereditary cancer-predisposing syndrome	2015-10-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000990030	SCV001140794	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410926	SCV001287319	likely benign	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759713	SCV001474040	benign	not provided	2022-03-07	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000759713	SCV002010893	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798360	SCV002043639	benign	Breast and/or ovarian cancer	2023-05-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000759713	SCV002063644	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRIP1: BP4, BS2
Genetic Services Laboratory, University of Chicago	RCV000120406	SCV002066921	benign	not specified	2019-02-27	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225334	SCV002505046	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116161	SCV002533720	benign	Hereditary cancer-predisposing syndrome	2020-10-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120406	SCV002551207	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001084461	SCV002801283	likely benign	Familial cancer of breast; Fanconi anemia complementation group J	2021-08-23	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000990030	SCV004016915	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000990030	SCV004019479	benign	Familial cancer of breast	2023-03-02	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV000759713	SCV005211185	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000120406	SCV000084558	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000116161	SCV000805254	likely benign	Hereditary cancer-predisposing syndrome	2018-05-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358435	SCV001554165	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Val193Ile variant was identified in 4 of 726 proband chromosomes (frequency: 0.006) from individuals with breast and prostate cancer and was present in 14 of 4556 control chromosomes (frequency: 0.003) from healthy individuals (Kote-Jarai 2009,Rutter 2003, Vahteristo 2006, Wong 2011). The variant was identified in dbSNP (rs4988346) as “with benign allele”, ClinVar (interpreted as "benign" by Invitae and 8 others and "likely benign" by True Health Diagnostics). The variant was identified in control databases in 986 of 277,084 chromosomes (9 homozygous) at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 13 of 24,026 chromosomes (freq: 0.0005), Other in 39 of 6462 chromosomes (freq: 0.006), Latino in 135 of 34,414 chromosomes (freq: 0.004), European in 650 of 126,616 chromosomes (freq: 0.005), Ashkenazi Jewish in 54 of 10,148 chromosomes (freq: 0.005), Finnish in 27 of 25,780 chromosomes (freq: 0.001), and South Asian in 68 of 30,782 chromosomes (freq: 0.002). The variant was not observed in the East Asian population. The p.Val193 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000759713	SCV001742962	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000759713	SCV001808455	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120406	SCV001906447	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000759713	SCV001931320	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000759713	SCV001955968	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120406	SCV002036294	benign	not specified		no assertion criteria provided	clinical testing