Submissions for variant NM_032043.3(BRIP1):c.3459T>C (p.Asp1153=)

gnomAD frequency: 0.00069  dbSNP: rs4987050

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212336	SCV000167439	benign	not specified	2013-11-06	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	RCV000124030	SCV000212952	likely benign	Hereditary cancer-predisposing syndrome	2014-07-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082541	SCV000253630	benign	Familial cancer of breast; Fanconi anemia complementation group J	2025-02-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000411782	SCV000404570	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000411782	SCV000489929	likely benign	Fanconi anemia complementation group J	2016-08-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000409837	SCV000489930	likely benign	Ovarian neoplasm	2016-08-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000124030	SCV000537409	likely benign	Hereditary cancer-predisposing syndrome	2015-04-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679785	SCV000602891	benign	not provided	2024-10-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679785	SCV000888002	benign	not provided	2022-10-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000989977	SCV001140739	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798415	SCV002043634	likely benign	Breast and/or ovarian cancer	2023-04-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212336	SCV002066910	benign	not specified	2021-02-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000124030	SCV002533694	likely benign	Hereditary cancer-predisposing syndrome	2021-02-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212336	SCV002551148	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000989977	SCV004019406	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	RCV000679785	SCV004145814	likely benign	not provided	2024-12-01	criteria provided, single submitter	clinical testing	BRIP1: BP4, BP7
True Health Diagnostics	RCV000124030	SCV000787969	likely benign	Hereditary cancer-predisposing syndrome	2017-11-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732693	SCV000807145	likely benign	BRIP1-related disorder	2024-05-31	no assertion criteria provided	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679785	SCV001548830	likely benign	not provided		no assertion criteria provided	clinical testing	The BRIP1 p.Asp1153= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, and Zhejiang University databases. The variant was identified in dbSNP (ID: rs4987050) as with uncertain significance allele, in the ClinVar database as benign by GeneDx, Invitae; as likely benign by Ambry Genetics, Counsyl, Color Genomics, Quest Diagnostics, Nichols Institute San Juan Capistrano and ARUP Laboratories; and with uncertain significance by Illumina Clinical Services. The variant was identified in control databases in 201 of 275956 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). In addition, the variant was identified in the1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and in the NHLBI GO Exome Sequencing Project in 6 of 8598 European American and in 1 of 4406 African American alleles. The variant was observed in the following populations: African in 3 of 24010 chromosomes (freq: 0.0001), Other in 18 of 6450 chromosomes (freq: 0.003), Latino in 36 of 34368 chromosomes (freq: 0.001), European Non-Finnish in 116 of 126504 chromosomes (freq: 0.001), Ashkenazi Jewish in 14 of 10146 chromosomes (freq: 0.001), and South Asian in 14 of 30730 chromosomes (freq: 0.0005), while the variant was not observed in the East Asian, European Finnish populations. The p.Asp1153= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.