chr17-61743106-A-G
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1
The NM_032043.3(BRIP1):c.2286T>C(p.Arg762=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,614,018 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 1 hom. )
Consequence
BRIP1
NM_032043.3 synonymous
NM_032043.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.51
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 -17 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
Variant 17-61743106-A-G is Benign according to our data. Variant chr17-61743106-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=2.51 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0016 (243/152318) while in subpopulation AFR AF= 0.00496 (206/41572). AF 95% confidence interval is 0.0044. There are 1 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2286T>C | p.Arg762= | synonymous_variant | 16/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2286T>C | p.Arg762= | synonymous_variant | 16/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00159 AC: 242AN: 152200Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000545 AC: 137AN: 251252Hom.: 1 AF XY: 0.000471 AC XY: 64AN XY: 135784
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GnomAD4 exome AF: 0.000254 AC: 371AN: 1461700Hom.: 1 Cov.: 31 AF XY: 0.000226 AC XY: 164AN XY: 727142
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GnomAD4 genome AF: 0.00160 AC: 243AN: 152318Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 124AN XY: 74462
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | BRIP1: BP4, BP7 - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2016 | Variant summary: The BRIP1 c.2286T>C variant affects a conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts a damaging outcome for this variant. 3/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect ESE site of SF2/ASF (IgM-BRCA1). However, these predictions have not been confirmed by experimental studies. This variant is found in 61/121286 control chromosomes (1 homozygote) at a frequency of 0.0005029, which is about 8 times the maximal expected frequency of a pathogenic BRIP1 allele (0.0000625), suggesting this variant is benign. In addition, multiple clinical laboratories classified this variant as likely benign/benign. Taken together, this variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 31, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 16, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 08, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jul 12, 2017 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 25, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2014 | 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. - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 19, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2014 | 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. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 11, 2017 | - - |
Fanconi anemia complementation group J Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 06, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
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 | May 01, 2023 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRIP1 p.Arg762= variant was identified in 1 of 188 proband chromosomes (frequency: 0.005) from individuals or families with prostate cancer (Ray 2009). The variant was also identified in the following databases, dbSNP (ID: rs61754141) as “With Uncertain significance allele”, ClinVar (7x, as benign by GeneDx, Invitae, as likely benign by Ambry Genetics, Counsyl, as uncertain significance by Illumina), Clinvitae (6x, with conflicting predictions as benign, likely benign and uncertain significance), Zhejiang Colon Cancer Database (1x with unknown pathogenicity). The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 179 of 276976 (1 homozygous) chromosomes at a frequency of 0.0006 in the following populations: African in 129 of 24038 (1 homozygous) chromosomes (freq. 0.005), other in 2 of 6462 chromosomes (freq. 0.0003), Latino in 25 of 34400 chromosomes (freq. 0.0007), European in 22 of 126538 chromosomes (freq. 0.0002), and South Asian in 1 of 30782 chromosomes (freq. 0.00003), increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The p.Arg762Arg variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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. - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 01, 2023 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
Ovarian neoplasm Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 06, 2016 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at