Submissions for variant NM_032043.3(BRIP1):c.2236A>G (p.Ile746Val)

gnomAD frequency: 0.00480  dbSNP: rs111536363

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084184	SCV000166678	benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000120395	SCV000167430	benign	not specified	2014-02-06	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	RCV000129045	SCV000172957	benign	Hereditary cancer-predisposing syndrome	2014-11-25	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.
Illumina Laboratory Services, Illumina	RCV000409120	SCV000404599	benign	Fanconi anemia complementation group J	2018-01-12	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000409120	SCV000489835	benign	Fanconi anemia complementation group J	2016-06-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000410719	SCV000489836	benign	Ovarian neoplasm	2016-06-08	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120395	SCV000593765	benign	not specified	2018-03-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129045	SCV000684196	likely benign	Hereditary cancer-predisposing syndrome	2015-04-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120395	SCV000807129	benign	not specified	2016-12-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120395	SCV000889211	benign	not specified	2021-03-02	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225367	SCV002505029	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120395	SCV002551176	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149826	SCV003837709	benign	Breast and/or ovarian cancer	2021-07-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315734	SCV004016916	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315734	SCV004019467	likely benign	Familial cancer of breast	2023-03-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Breakthrough Genomics, Breakthrough Genomics	RCV004704870	SCV005211178	likely benign	not provided		criteria provided, single submitter	not provided
CeGaT Center for Human Genetics Tuebingen	RCV004704870	SCV005330981	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRIP1: BP4, BS1
ITMI	RCV000120395	SCV000084547	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356261	SCV001551378	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Ile746Val variant was identified in 3 of 7992 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch or ovarian cancer and was present in 4 of 8224 control chromosomes (frequency: 0.0005) from healthy individuals (Ramus 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs111536363) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Ambry Genetics, Counsyl and two clinical laboratories; as likely benign by tree clincal laboratories), MutDB, and in Zhejiang University, databases. The variant was not identified in Cosmic, database. The variant was identified in control databases in 387 of 276970 chromosomes (6 homozygous) at a frequency of 0.001 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 361 of 24026 chromosomes (freq: 0.01), Other in 2 of 6462 chromosomes (freq: 0.0003), Latino in 18 of 34408 chromosomes (freq: 0.0005), European in 3 of 126534 chromosomes (freq: 0.00002), East Asian in 1 of 18864 chromosomes (freq: 0.00005), and South Asian in 2 of 30744 chromosomes (freq: 0.00007), while the variant was not observed in the Ashkenazi Jewish, and Finnish, populations. The p.Ile746 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120395	SCV001905682	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000120395	SCV001963705	benign	not specified		no assertion criteria provided	clinical testing