Submissions for variant NM_032043.3(BRIP1):c.2441G>A (p.Arg814His)

gnomAD frequency: 0.00001  dbSNP: rs45468199

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130375	SCV000185229	likely benign	Hereditary cancer-predisposing syndrome	2020-11-04	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.
GeneDx	RCV000218503	SCV000278902	uncertain significance	not provided	2023-08-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and also in unaffected controls (Seal et al., 2006; Easton et al., 2016; Bhai et al., 2021; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 24705251, 30093976, 26921362, 22722202, 17033622, 29596542, 32566746, 34326862, 33471991)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234009	SCV000291014	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 814 of the BRIP1 protein (p.Arg814His). This variant is present in population databases (rs45468199, gnomAD 0.008%). This missense change has been observed in individual(s) with lymphoma, paraganglioma, breast and/or colon cancer (PMID: 17033622, 26921362, 29596542, 30093976). ClinVar contains an entry for this variant (Variation ID: 141744). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000410258	SCV000490105	uncertain significance	Fanconi anemia complementation group J	2016-11-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000411419	SCV000490106	uncertain significance	Ovarian neoplasm	2016-11-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130375	SCV000911528	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 814 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 17033622, 26921362) and in one individual each affected with pancreatic cancer (PMID: 36896836) and colorectal cancer (PMID: 30093976). This variant also has been detected in a breast cancer case-control meta-analysis in 10/60466 cases and 10/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000227) and in a prostate cancer case-control study in 1/7636 cases and absent in 12366 unaffected individuals (PMID: 31214711). This variant has been identified in 8/250268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030534	SCV001193530	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218503	SCV001469731	uncertain significance	not provided	2020-05-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130375	SCV002533626	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-06	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315890	SCV004019416	uncertain significance	Familial cancer of breast	2023-03-01	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320104	SCV004024305	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003315890	SCV004217117	uncertain significance	Familial cancer of breast	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356230	SCV001551344	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Arg814His variant was identified in 3 of 28850 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer and was not identified in 14646 control chromosomes from healthy individuals (Easton 2016, Seal 2006). The variant was also identified in dbSNP (ID: rs45468199) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and Counsyl). The variant was identified in control databases in 9 of 245184 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 9 of 111266 chromosomes (freq: 0.00008), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg814 residue is 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.