rs28997569
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_032043.3(BRIP1):c.790C>T(p.Arg264Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,613,856 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 3 hom. )
Consequence
BRIP1
NM_032043.3 missense
NM_032043.3 missense
Scores
5
8
6
Clinical Significance
Conservation
PhyloP100: 3.66
Genes affected
BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.041837633).
BP6
Variant 17-61808595-G-A is Benign according to our data. Variant chr17-61808595-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128195.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=15, not_provided=1, Benign=1, Uncertain_significance=3}. Variant chr17-61808595-G-A is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRIP1 | NM_032043.3 | c.790C>T | p.Arg264Trp | missense_variant | 7/20 | ENST00000259008.7 | NP_114432.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRIP1 | ENST00000259008.7 | c.790C>T | p.Arg264Trp | missense_variant | 7/20 | 1 | NM_032043.3 | ENSP00000259008 | P2 |
Frequencies
GnomAD3 genomes 0.00100 AC: 152AN: 152004Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000828 AC: 208AN: 251076Hom.: 0 AF XY: 0.000877 AC XY: 119AN XY: 135670
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GnomAD4 exome AF: 0.00118 AC: 1719AN: 1461734Hom.: 3 Cov.: 31 AF XY: 0.00117 AC XY: 853AN XY: 727172
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GnomAD4 genome 0.000999 AC: 152AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62AN XY: 74390
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:19Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | research | University of Washington Department of Laboratory Medicine, University of Washington | Mar 28, 2018 | The BRIP1 variant designated as NM_032043.2:c.790C>T (p.Arg264Trp) is now classified as likely benign. The variant is present in approximately 1 in 500 individuals in European and African populations (exac.broadinstitute.org). This population frequency is not consistent with a high-risk cancer variant. In addition, there are no reports of pathogenic missense variants in this BRIP1 protein domain. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 128195). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BRIP1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 02, 2023 | 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:2Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 02, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
not provided Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 23, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 03, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | BRIP1: BP1 - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 08, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2018 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 22, 2015 | - - |
Fanconi anemia complementation group J Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Jul 18, 2016 | - - |
Malignant tumor of breast Benign:2
| Benign, no assertion criteria provided | clinical testing | Center of Medical Genetics and Primary Health Care | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRIP1 p.Arg264Trp variant was identified in 55 of 46810 proband chromosomes (frequency: 0.001) from Italian, American, British and Colombian individuals or families with a wide spectrum of cancers (in population based studies, unselected for family history): BRCA1/2 negative, male/female breast cancer, prostate cancer, ovarian cancer, Lynch syndrome associated cancer and/or polyps, CRC, pancreatic cancer, hereditary prostate cancer and Fanconi anemia; and was present in 44 of 29724 control chromosomes (frequency: 0.001) from healthy individuals (Silvestri_2011_21165771, Bodian_2014_24728327, Hu_2016_26483394, Yurgelun_2015_25980754, Tung_20016_26976419, Seal_2006_17033622, Easton_2016_26921362, Levitus_2005_16116423, Pearlman_2016_27978560, Ramus_2015_26315354, Cock-Rada_2017_28528518, Ray_2009_19935797). In one prostate cancer family, the variant was identified in two out of three cases and was not present in the unaffected brother of the proband (Ray_2009_19935797). In 1 male proband with breast cancer, diagnosed at 76 yrs of age, DNA extracted from the micro-dissected breast tumor sample showed that no loss of the wild-type allele had occurred in tumor cells (Silvestri_2011_21165771). The variant was identified in dbSNP (ID: rs28997569) “With Likely benign allele”, ClinVar (classified likely benign by Invitae, Ambry Genetics, Genetic Services Laboratory (University of Washington), Counsyl, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, and GeneDx, and classification not provided by ITMI), Clinvitae (5x) and Zhejiang Colon Cancer Database, and was not identified in Cosmic or MutDB. The variant was also identified in control databases in 229 of 276746 chromosomes at a frequency of 0.0008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 17 of 24030 chromosomes (freq: 0.0007), “Other” in 11 of 6452 chromosomes (freq: 0.002), Latino in 15 of 34408 chromosomes (freq: 0.0004), European Non-Finnish in 145 of 126288 chromosomes (freq: 0.001), Ashkenazi Jewish in 28 of 10142 chromosomes (freq: 0.003), European Finnish in 7 of 25786 chromosomes (freq: 0.0003), and South Asian in 6 of 30782 chromosomes (freq: 0.0002); it was not observed in the East Asian population. The p.Arg264 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp variant 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 21, 2023 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
BRIP1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 28, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Ovarian neoplasm Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Jul 18, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at