Submissions for variant NM_032043.3(BRIP1):c.139C>G (p.Pro47Ala)

gnomAD frequency: 0.00024  dbSNP: rs28903098

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587908	SCV000150033	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast, ovarian, or pancreatic cancer, but also in controls and in individuals with pathogenic variants in other genes explaining their phenotype (Cantor et al., 2001; Seal et al., 2006; Kanchi et al., 2014; Yurgelun et al., 2015; Pinto et al., 2016; Schrader et al., 2016; Pearlman et al., 2017; Weber-Lasalle et al., 2018; Hu et al., 2020; Bhai et al., 2021; Dorling et al., 2021; Zuntini et al., 2021); Published functional studies demonstrate abolished ATPase activity, weakened helicase activity, and decreased protein stability compared to wild-type (Cantor et al., 2001; Cantor et al., 2004; Gupta et al., 2006; Gupta et al., 2007; Wu et al., 2008; Moyer et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22792074, 16430786, 27621404, 31159747, 20658644, 21345144, 16280053, 18628483, 25980754, 18483852, 19379763, 25374583, 23276657, 19519404, 15855896, 26790966, 26264438, 17145708, 24448499, 17033622, 26315354, 18426915, 11301010, 14983014, 17596542, 27553368, 27978560, 26709662, 28911102, 28135136, 26556299, 28767289, 25186627, 29368626, 31422574, 31512090, 31822495, 33028645, 32659497, 33980423, 34072463, 33546375, 34426522, 28104920, 30613976, 35734982, 26681312, 35264596, 33471991, 25452441, 35205822, 34326862)
Ambry Genetics	RCV000116124	SCV000186330	likely benign	Hereditary cancer-predisposing syndrome	2022-07-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000199377	SCV000255146	likely benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000409748	SCV000489947	uncertain significance	Fanconi anemia complementation group J	2016-08-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000410864	SCV000489948	uncertain significance	Neoplasm of ovary	2016-08-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587908	SCV000600892	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 26681312 (2015), 26921362 (2016), 33471991 (2021)), ovarian cancer (PMIDs: 24448499 (2014), 26681312 (2015)), hematologic cancer (PMID: 26681312 (2015)), pancreatic cancer (PMID: 35205822 (2022)), colorectal cancer (PMIDs: 27978560 (2016), 35734982 (2022)), glioma (PMID: 26264438 (2016)), and unaffected individuals (PMIDs: 24448499 (2014), 26921362 (2016), 26921362 (2016), 33471991 (2021)). Co-occurrences of this variant with other pathogenic variants in individuals with BRIP1-realted conditions have been reported in the literature (PMIDs: 27553368 (2016), 27978560 (2016), 34072463 (2021), Quest internal data). Assessment of experimental evidence indicates this variant has deleterious effects on protein function (PMIDs: 11301010 (2001), 14983014 (2004), 17033622 (2006), 17145708 (2006), 28911102 (2017), 31822495 (2019)). The frequency of this variant in the general population, 0.00048 (62/129132 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200979	SCV000699663	likely benign	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.139C>G (p.Pro47Ala) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain, DinG/Rad3-type and Helicase-like, DEXD box c2 type of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 257860 control chromosomes, predominantly at a frequency of 0.00047 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Consistent with its high frequency in the control databases, c.139C>G has been widely reported in the literature in sequencing studies of individuals affected with cancer including breast and ovarian cancer, colorectal cancer and pancreatic cancer and also in unaffected controls. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Several co-occurrences with other pathogenic variant(s) have been reported in the literature (CHEK2 c.846+4_846+7delAGTA; BRCA1 c.5266dup, p.Gln1756ProfsX74; PALB2 c.1240C>T, p.Arg414X; BRCA2 c.8327T>G, p.L2776X; MSH2 c.942+3A>T), providing additional supporting evidence for a benign role (Pinto_2016, Schrader_2016, Pearlman_2016). Several publications report experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Based on these results, the variant may reduce ATPase and helicase functions, however, mutant protein is fully soluble and can still interact with BRCA1. Therefore, the variant's role in tumorigenesis remains unclear. The following publications have been ascertained in the context of this evaluation (PMID: 27621404, 11301010, 14983014, 25452441, 26921362, 17596542, 17145708, 24448499, 26264438, 26822949, 27978560, 27553368, 21964575, 26315354, 31512090, 26556299, 17033622, 28767289, 26681312, 25186627, 29368626, 18426915, 25980754, NO_PMID, 35534704). Twenty two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1), likely benign (n=4), and VUS (n=17). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA	RCV000116124	SCV000821954	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000409748	SCV000839405	uncertain significance	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000199377	SCV000895119	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116124	SCV000902624	likely benign	Hereditary cancer-predisposing syndrome	2016-06-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778130	SCV000914255	uncertain significance	BRIP1-Related Disorders	2019-04-05	criteria provided, single submitter	clinical testing	The BRIP1 c.139C>G (p.Pro47Ala) variant has been reported in two studies in which it is found in a heterozygous state in a total of five patients, all with a family history of breast cancer (Cantor et al. 2001; Seal et al. 2006). Only the BRIP1 gene was screened in both studies. The p.Pro47Ala variant was also detected in a heterozygous state in four of 2081 controls who were 46 years of age at the time of study (Seal et al. 2006). Based on age of the individuals, disease status cannot be fully determined in the control cohort. Additionally, the p.Pro47Ala variant is reported at a frequency of 0.00038 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in cultured cells demonstrated that the p.Pro47Ala variant protein has a reduced half-life compared to wild type protein and also exhibits complete loss of ATPase and helicase activity (Cantor et al. 2001; Cantor et al. 2004). The evidence for this variant is limited. The p.Pro47Ala variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for BRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics	RCV000990044	SCV001140808	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000409748	SCV001367307	uncertain significance	Fanconi anemia complementation group J	2019-09-16	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
CeGaT Center for Human Genetics Tuebingen	RCV000587908	SCV001501681	uncertain significance	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587908	SCV002010922	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587908	SCV002048512	uncertain significance	not provided	2021-09-17	criteria provided, single submitter	clinical testing	The BRIP1 c.139C>G; p.Pro47Ala variant (rs28903098) is reported in the literature in several individuals with breast and ovarian cancer syndrome, including some co-occurrences with pathogenic variants in other known cancer-associated genes, and has also been reported in healthy controls (Cantor 2001, Easton 2016, Kanchi 2014, Pearlman 2017, Rafnar 2011, Schrader 2016, Susswein 2016, Weber-Lassalle 2018). In vitro functional assays have shown the variant protein to have impaired helicase and ATPase activities (Cantor 2004, Gupta 2006, Wu 2008), but is also noted as a hypermorphic allele (Kraemer 2019, Moyer 2020). This variant is reported in ClinVar (Variation ID: 4736), and is found in the general population with an overall allele frequency of 0.0025% (72/282802 alleles, including a single homozygote) in the Genome Aggregation Database. The proline at codon 47 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.698). Based on available information, the clinical significance of p.Pro47Ala is uncertain at this time. References: Cantor SB et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001 Apr 6;105(1):149-60. PMID: 11301010. Cantor S et al. The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2357-62. PMID: 14983014. Easton DF et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet. 2016 May;53(5):298-309. PMID: 26921362. Gupta R et al. Inhibition of BACH1 (FANCJ) helicase by backbone discontinuity is overcome by increased motor ATPase or length of loading strand. Nucleic Acids Res. 2006;34(22):6673-83. PMID: 17145708. Kanchi KL et al. Integrated analysis of germline and somatic variants in ovarian cancer. Nat Commun. 2014;5:3156. PMID: 24448499. Kraemer D et al. Prevalence of genetic susceptibility for breast and ovarian cancer in a non-cancer related study population: secondary germline findings from a Swiss single centre cohort. Swiss Med Wkly. 2019 Aug 18;149:w20092. PMID: 31422574. Moyer CL et al. Rare BRIP1 Missense Alleles Confer Risk for Ovarian and Breast Cancer. Cancer Res. 2020 Feb 15;80(4):857-867. PMID: 31822495. Pearlman R et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017 Apr 1;3(4):464-471. PMID: 27978560. Rafnar T et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet. 2011 Oct 2;43(11):1104-7. PMID: 21964575. Schrader KA et al. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol. 2016 Jan;2(1):104-11. PMID: 26556299. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. PMID: 26681312. Weber-Lassalle N et al. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. Breast Cancer Res. 2018 Jan 24;20(1):7. PMID: 29368626. Wu Y et al. FANCJ helicase defective in Fanconia anemia and breast cancer unwinds G-quadruplex DNA to defend genomic stability. Mol Cell Biol. 2008 Jun;28(12):4116-28. PMID: 18426915.
Sema4, Sema4	RCV000116124	SCV002531346	likely benign	Hereditary cancer-predisposing syndrome	2021-06-30	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000990044	SCV002556832	uncertain significance	Familial cancer of breast	2020-11-04	criteria provided, single submitter	clinical testing	VUS. Although first identified in a patient with early onset familial breast cancer and with functional data and computational predictions suggesting possibly pathogenicity. The variant has not been shown to segregate with disease, has not been identified in several large studies and has been seen in both controls and cases. NB Given as an example of variant reported with conflicting classification by diagnostic labs (PMID:27621404)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149563	SCV003837721	uncertain significance	Breast and/or ovarian cancer	2021-06-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000990044	SCV004019461	uncertain significance	Familial cancer of breast	2023-03-02	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	RCV000200979	SCV004026896	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000409748	SCV004234879	uncertain significance	Fanconi anemia complementation group J	2023-06-05	criteria provided, single submitter	clinical testing
OMIM	RCV000005002	SCV000025178	pathogenic	Breast cancer, early-onset	2019-04-19	no assertion criteria provided	literature only
Clinical Cancer Genetics and Family Consultants, Athens Medical Center	RCV001090025	SCV001167103	pathogenic	Malignant tumor of breast	2019-04-19	no assertion criteria provided	clinical testing	This variant denoted BRIP1 c.139C>G at the DNA level, p.Pro47Ala at the protein level, was first described in a young woman with family history of Breast cancer ( Cantor SB. 2001 PMID:11301010 , R. Litman 2008 PMID: 18473727 , Cantor SB. 2011 https://doi.org/10.2217/fon.10.191). The laboratory data indicated that the mutant protein was less stable than wild type and/or other negative mutant products and was characterized as functionally defective. The mutant protein was found to be very rare. They considered these findings as evidence of pathogenicity of the mutant BRIP1 protein and therefore clinically relevant on that patient. This is a rare variant at a frequency of 0.00024 in ExAC and was reported so far in patients with hereditary ovarian and colorectal cancers, as well as in healthy controls. There are so far 18 entries in ClinVar and most of them classify this variant as a VUS with the exception of the most recent report (Apr )19,2019,OMIM which classifies this mutation as pathogenic. We found this germline mutation, P47A, in a 23 year old woman with triple negative breast cancer. Our patient's pedigree was very short on both sides, and inheritance could not be documented. The helicase activity of the P47A mutant protein is defective, as described by Cantor, and BRIP1 is an interacting BRCA1 protein, we consider this mutation to be clinically important and treatment target in our patient. We published evidence that patients with metastatic TNBC respond to treatment with Cis-Platinum regimens ( DOI:10.1081/cnv-120022358, doi.org/10.1081/CNV-120022358), and 5-8 % obtain a complete remission. We treated this patient with Liver, CNS, Lymph nodes metastatic disease with cis -platinum ant the patient obtained a complete remission lasting so far for 50 months. The importance of this report lies on the fact and supports clinical evidence that BRIP1 P47A mutation may represent a site specific helicase target for Cis-platinum treatment in breast cancer.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001090025	SCV001550127	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Pro47Ala variant was identified in 9 of 7380 proband chromosomes (frequency: 0.001) from American, British and Australian individuals or families with BRCA1/2 negative breast cancer (early onset, familial), ovarian cancer or Lynch syndrome associated cancer and was identified in 5 of 5676 chromosomes (frequency: 0.001) from healthy individuals (Yurgelun 2015, Seal 2006, Cantor 2001, Lewis 2005, Kanchi 2014, Balmana 2016). The variant alters a highly conserved residue and functional assays showed a considerably reduced and less stable mutant transcript, while enzymatic activity looking at unwinding of forked duplexes showed helicase activity was devoid (Cantor 2001, Gupta 2006). The variant was identified as a rare missense variant in 1 individual with early onset breast cancer with a strong family history of breast and ovarian cancer, but segregation studies were not performed (Cantor 2001). This variant has conflicting interpretations of pathogenicity in the literature and may be considered a low penetrant allele (Balmana 2016). The variant was identified in dbSNP (ID: rs28903098), ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, and Quest Diagnostics; pathogenic by OMIM; and likely pathogenic by University of Chicago), Clinvitae, Zhejiang Colon Cancer Database (2x, pathogenicity unknown), and was not identified in Cosmic and MutDB. The variant was identified in control databases in 69 (1 homozygous) of 277164 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 2 of 6464 chromosomes (freq: 0.0003), Latino in 5 of 34420 chromosomes (freq: 0.0001), European Non-Finnish in 59 (1 homozygous) of 126662 chromosomes (freq: 0.0005), European Finnish in 1 of 25788 chromosomes (freq: 0.00004), and South Asian in 2 of 30778 chromosomes (freq: 0.00007); it was not observed in the African, Ashkenazi Jewish, and East Asian populations. The p.Pro47 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant Ala may impact the protein; however, this information is not predictive enough to assume 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587908	SCV001740462	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000587908	SCV001798619	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587908	SCV001906194	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000587908	SCV001926306	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587908	SCV001957666	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000005002	SCV002069035	uncertain significance	Breast cancer, early-onset	2021-12-02	no assertion criteria provided	clinical testing	DNA sequence analysis of the BRIP1 gene demonstrated a sequence change, c.139C>G, in exon 3 that results in an amino acid change, p.Pro47Ala. This sequence change has been described in the gnomAD database with a frequency of 0.048% in European populations and in one individual in homozygous state (dbSNP rs28903098). Functional studies demonstrated that the p.Pro47Ala change has an impact on protein function and is shown to have reduced ATPase activity, helicase deficiency and decreased protein stability; however, it is unclear if this reduced function translates to a clinical phenotype (PMIDs: 14983014, 31822495, 11301010). The p.Pro47Ala change has been identified in individuals with personal or family history of colon cancer, breast cancer, ovarian cancer and pancreatic ductal adenocarcinoma (PMID: 27978560, 11301010, 28767289, 24448499, 31159747, 17596542) but has also been identified in control populations. It has also shown to co-occur with pathogenic variants in other genes (PMIDs: 27978560, 27553368, 26556299). The p.Pro47Ala change affects a highly conserved amino acid residue located in a domain of the BRIP1 protein that is known to be functional. The p.Pro47Ala substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence, the clinical significance of the p.Pro47Ala change remains unknown at this time.