ClinVar Miner

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

gnomAD frequency: 0.00024  dbSNP: rs28903098
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Total submissions: 29
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587908 SCV000150033 uncertain significance not provided 2022-08-05 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 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; 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, 27535533, 34426522, 28104920, 30613976)
Ambry Genetics RCV000116124 SCV000186330 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-14 criteria provided, single submitter clinical testing The p.P47A variant (also known as c.139C>G), located in coding exon 2 of the BRIP1 gene, results from a C to G substitution at nucleotide position 139. The proline at codon 47 is replaced by alanine, an amino acid with highly similar properties. This alteration has been detected in individuals with suspected hereditary breast and/or ovarian cancer (Cantor SB et al. Cell. 2001 Apr;105:149-60; Tung N et al. Cancer. 2015 Jan;121:25-33; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Schrader KA et al. JAMA Oncol. 2016 Jan;2:104-11; Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159:245-56; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). In a study of 81 men with breast cancer, this variant was reported in one case who was diagnosed at age 67 without additional personal or family history of cancer reported (Scarpitta R et al. Breast Cancer Res. Treat. 2019 Dec;178:557-564). However, this variant has not been associated with disease in several case-control studies (Rafnar T et al. Nat. Genet. 2011 Oct;43:1104-7; Kanchi KL et al. Nat. Commun. 2014;5:3156; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107; Easton DF et al. J. Med. Genet. 2016 May;53:298-309). Additionally, this variant has been absent in several familial breast cancer cohorts (Rutter JL et al. Hum. Mutat. 2003 Aug;22:121-8; Lewis AG et al. Breast Cancer Res. 2005;7:R1005-16; De Nicolo A et al. Clin. Cancer Res. 2008 Jul;14:4672-80). Although it appears that this alteration results in reduced protein expression (Cantor SB et al. Cell. 2001 Apr;105:149-60; Gupta R et al. Blood. 2007 Oct;110:2390-8; Nath S et al. Nucleic Acids Res. 2017 Sep;45:8886-8900) and dramatically reduced ATPase and helicase function (Cantor S et al. Proc. Natl. Acad. Sci. U.S.A. 2004 Feb;101:2357-62; Gupta R et al. Nucleic Acids Res. 2006;34:6673-83; Gupta R et al. Blood. 2007 Oct;110:2390-8; Wu Y et al. Mol. Cell. Biol. 2008 Jun;28:4116-28), the significance of these impairments are difficult to interpret in light of a moderate-penetrance gene (Cantor SB et al. Future Oncol. 2011 Feb;7:253-61). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000199377 SCV000255146 likely benign Familial cancer of breast; Fanconi anemia complementation group J 2021-12-17 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
Genetic Services Laboratory,University of Chicago RCV000005002 SCV000593776 uncertain significance Breast cancer, early-onset 2018-01-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587908 SCV000600892 uncertain significance not provided 2020-06-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200979 SCV000699663 likely benign not specified 2021-01-09 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 homozygote. 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 (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. Multiple submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments, at-least two of whom support a likely benign outcome. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the limited actionable evidence supporting a causative outcome in an inherited context as outlined above and the moderate penetrance associated with variation in the BRIP1 gene, this variant was re-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 RCV000990044 SCV002010922 uncertain significance Familial cancer of breast 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.
Genetic Services Laboratory,University of Chicago RCV000200979 SCV002069035 uncertain significance not specified 2021-12-02 criteria provided, single submitter clinical testing
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)
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

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