chr17-61859862-G-C
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_032043.3(BRIP1):c.139C>G(p.Pro47Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,613,850 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000230 AC: 35AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000247 AC: 62AN: 251410Hom.: 1 AF XY: 0.000265 AC XY: 36AN XY: 135868
GnomAD4 exome AF: 0.000368 AC: 538AN: 1461574Hom.: 1 Cov.: 30 AF XY: 0.000396 AC XY: 288AN XY: 727094
GnomAD4 genome 0.000230 AC: 35AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:8Benign:1
Published functional studies demonstrate abolished ATPase activity, weakened helicase activity, and decreased protein stability compared to wild-type (PMID: 14983014, 11301010, 17596542, 17145708, 18426915, 31822495); 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 (PMID: 11301010, 17033622, 24448499, 25980754, 27553368, 29368626, 32659497, 26556299, 27978560, 34072463, 35534704); 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, 35534704, 37216690, 37869077, 38103590) -
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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. -
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BRIP1: PS3:Moderate, PP3, BP1, BS1 -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
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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. -
Fanconi anemia complementation group J Uncertain:3
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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. -
Familial cancer of breast Uncertain:3
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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) -
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. -
not specified Uncertain:1Benign:2
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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 8 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). 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, 35534704). ClinVar contains an entry for this variant (Variation ID: 4736). Based on the evidence outlined above, the variant was classified as likely benign. -
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Malignant tumor of breast Pathogenic:1Uncertain:1
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. -
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. -
Breast cancer, early-onset Pathogenic:1Uncertain:1
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. -
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Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1Benign:1
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Breast and/or ovarian cancer Uncertain:1
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BRIP1-related disorder Uncertain:1
The BRIP1 c.139C>G variant is predicted to result in the amino acid substitution p.Pro47Ala. This variant has been reported in individuals with a history of breast and ovarian cancers (Cantor et al. 2001. PubMed ID: 11301010; Seal et al. 2006. PubMed ID: 17033622; Kanchi et al. 2014. PubMed ID: 24448499; Rafnar et al. 2011. PubMed ID: 21964575, supplementary table 5) as well as unaffected control cohorts (Seal et al. 2006. PubMed ID: 17033622; Kanchi et al. 2014. PubMed ID: 24448499; Rafnar et al. 2011. PubMed ID: 21964575, supplementary table 5). In vitro functional studies suggest this variant impacts BRIP1 ATPase and helicase activities (Cantor et al. 2004. PubMed ID: 14983014). This variant is reported in 0.048% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4736). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Ovarian neoplasm Uncertain:1
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Hereditary breast ovarian cancer syndrome Benign:1
According to the ACMG SVI adaptation criteria we chose these criteria: PP3 (supporting pathogenic): REVEL: 0.698; BayesDEL: 0,257046; phyloP100: 8.458, BS1 (strong benign): gnomAD NFE: 0.000411619, BS2 (strong benign): 5x in Flossies -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at