Submissions for variant NM_032043.3(BRIP1):c.584T>C (p.Leu195Pro)

gnomAD frequency: 0.00197  dbSNP: rs4988347

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120407	SCV000150071	benign	not specified	2017-12-21	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	RCV001082551	SCV000166684	benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116162	SCV000172953	benign	Hereditary cancer-predisposing syndrome	2017-12-08	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.
Counsyl	RCV000410203	SCV000489853	likely benign	Fanconi anemia complementation group J	2016-07-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000411259	SCV000489854	likely benign	Ovarian neoplasm	2016-07-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589840	SCV000699730	benign	not provided	2016-02-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120407	SCV000889221	benign	not specified	2021-03-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116162	SCV000910543	likely benign	Hereditary cancer-predisposing syndrome	2014-12-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000990029	SCV001140793	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000410203	SCV001157291	benign	Fanconi anemia complementation group J	2019-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410203	SCV001287318	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798361	SCV002043640	likely benign	Breast and/or ovarian cancer	2023-03-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120407	SCV002066143	likely benign	not specified	2021-10-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116162	SCV002533721	benign	Hereditary cancer-predisposing syndrome	2021-03-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120407	SCV002551206	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116162	SCV002819151	benign	Hereditary cancer-predisposing syndrome	2022-12-23	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000990029	SCV004016923	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589840	SCV004145821	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	BRIP1: BP4
Myriad Genetics, Inc.	RCV000990029	SCV005404126	likely benign	Familial cancer of breast	2024-08-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign. 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.
ITMI	RCV000120407	SCV000084559	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV004528812	SCV000807154	benign	BRIP1-related disorder	2020-02-05	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589840	SCV001550148	likely benign	not provided		no assertion criteria provided	clinical testing	The BRIP1 p.Leu195Pro variant was identified in 21 of 13772 proband chromosomes (frequency: 0.002) from individuals or families with prostate cancer, breast cancer, ovarian cancer, and Lynch syndrome and was present in 19 of 21561 control chromosomes (frequency: 0.0009) from healthy individuals (Bodian 2014, Kote-Jarai 2009, Kuusisto 2011, Lewis 2005, Rafnar 2011, Ramus 2015, Ray 2009, Rutter 2003, Seal 2006, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs4988347) as "With Likely benign allele", ClinVar (4x benign, 3x likely benign), Clinvitae, and the Zhejiang Colon Cancer Database (6x, likely neutral). The variant was not identified in Cosmic or the MutDB database. The variant was identified in control databases in 537 of 277082 chromosomes (2 homozygous) at a frequency of 0.002 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 8 of 24028 chromosomes (freq: 0.0003), Other in 10 of 6464 chromosomes (freq: 0.002), Latino in 24 of 34414 chromosomes (freq: 0.0007), European in 255 of 126622 chromosomes (freq: 0.002), Finnish in 226 of 25772 chromosomes (freq: 0.009), and South Asian in 14 of 30782 chromosomes (freq: 0.0005). The variant was not observed in the Ashkenazi Jewish or East Asian populations. A study by Lewis 2005 utilizing in silico bioinformatic tools predicted this variant may affect mRNA folding and exonic splicing enhancers. However, the same study showed that the variant did not segregate with disease in a family with breast cancer (Lewis 2005). The p.Leu195 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000589840	SCV001807087	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000589840	SCV001906038	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589840	SCV001960027	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589840	SCV001964912	likely benign	not provided		no assertion criteria provided	clinical testing