Submissions for variant NM_032043.3(BRIP1):c.3103C>T (p.Arg1035Cys)

gnomAD frequency: 0.00006  dbSNP: rs45437094

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129008	SCV000172905	benign	Hereditary cancer-predisposing syndrome	2022-09-29	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Invitae	RCV001081667	SCV000253627	likely benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000590794	SCV000279384	likely benign	not provided	2021-01-29	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26315354, 26921362, 25722345, 21279724, 17033622)
Counsyl	RCV000410906	SCV000490057	uncertain significance	Fanconi anemia complementation group J	2016-10-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000412441	SCV000490058	uncertain significance	Neoplasm of ovary	2016-10-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590794	SCV000699713	benign	not provided	2016-05-27	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.3103C>T (p.Arg1035Cys) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome. This variant was found in 72/125562 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0039976 (66/16510). This frequency is about 64 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), highly suggesting this is a benign polymorphism found primarily in the populations of South Asian origin. Additionally, the variant of interest was found to co-occur with a likely pathogenic PALB2 variant, c.829_832delGACC, in one internal LCA specimen. Furthermore, one clinical diagnostic laboratory recently classified this variant as likely benign. Taken together, this variant is classified as Benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590794	SCV000885118	uncertain significance	not provided	2017-09-06	criteria provided, single submitter	clinical testing	The p.Arg1035Cys variant (rs45437094) has been reported in the medical literature in at least one case of non-serous ovarian cancer (Ramus 2015). The p.Arg1035Cys variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.48% in the South Asian population (identified in 135 out of 30,782 chromosomes; 0 homozygotes), and is listed in ClinVar (likely benign/uncertain significance; Variant ID: 140819). The arginine at codon 1,035 is weakly conserved considering 12 species (Alamut software v2.9.0), and computational analyses suggest that this variant does not affect the Brip1 protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). While the p.Arg1035Cys appears to be a benign polymorphism in the South Asian population, the available information is insufficient to determine the clinical significance with certainty.
Color Diagnostics, LLC DBA Color Health	RCV000129008	SCV000910605	likely benign	Hereditary cancer-predisposing syndrome	2015-07-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410906	SCV001284863	uncertain significance	Fanconi anemia complementation group J	2018-01-15	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800423	SCV002046314	benign	not specified	2020-10-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001800423	SCV002068138	uncertain significance	not specified	2020-12-03	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRIP1 gene demonstrated a sequence change, c.3103C>T, in exon 20 that results in an amino acid change, p.Arg1035Cys. This sequence change does not appear to have been previously described in patients with BRIP1-related disorders and has been described in the gnomAD database with a frequency of 0.44% in the South Asian sub-population (dbSNP rs45437094). The p.Arg1035Cys change affects a poorly conserved amino acid residue located in a domain of the BRIP1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1035Cys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1035Cys change remains unknown at this time.
Sema4, Sema4	RCV000129008	SCV002533677	likely benign	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001800423	SCV002551152	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149886	SCV003838374	likely benign	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590794	SCV004009820	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	BRIP1: BP4, BS2
Myriad Genetics, Inc.	RCV003315867	SCV004019402	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.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003315867	SCV004048178	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing	The missense variant p.R1035C in BRIP1 (NM_032043.3) has been reported previously in 2/189 Turkmen patients with esophageal squamous cell carcinoma (Akbari MR et al, 2011) and in a Caucasian patient diagnosed with a pancreatic neuroendocrine tumor (Shindo K et al, 2017). Variants in gene BRIP1 have been observed in individuals affected with Ovarian Cancer (Moyer et al, 2020 ). There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico tools predict the variant to be tolerated. For these reasons, this variant has been classified as Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003917414	SCV004732054	benign	BRIP1-related condition	2019-07-09	criteria provided, single submitter	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	RCV001355322	SCV001550180	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Arg1035Cys variant was identified in 1 of 26426 proband chromosomes (frequency: 3.78 E-05) from individuals or families with breast cancer and was not identified in 10484 control chromosomes from healthy individuals (Easton 2016). The variant was also identified in the following databases: dbSNP (ID: rs45437094) as With Uncertain significance allele, ClinVar with conflicting interpretations of pathogenicity (as likely benign by Invitae, and as uncertain significance by Ambry Genetics, Gene Dx and Counsyl), Clinvitae (5x), and Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 149 of 277168 chromosomes at a frequency of 0.000538 in the following populations: South Asian in 135 of 30782 chromosomes (freq. 0.004), Other in 149 of 6466 chromosomes (freq. 0.00016), European (Non-Finnish) in 11 of 126676 chromosomes (freq. 0.000087), East Asian in 1 of 18858 chromosomes (freq. 0.00005), and Latino in 1 of 34418 chromosomes (freq. 0.000029) (Genome Aggregation Consortium Feb 27, 2017). The p.Arg1035Cys 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. This variant is classified as a variant of uncertain significance.