17-61776394-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000259008.7(BRIP1):​c.2097+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,980 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0030 ( 13 hom. )

Consequence

BRIP1
ENST00000259008.7 splice_region, intron

Scores

2
Splicing: ADA: 0.00007669
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:25

Conservation

PhyloP100: 0.00700
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 17-61776394-C-T is Benign according to our data. Variant chr17-61776394-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136147.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Uncertain_significance=1, Likely_benign=10}. Variant chr17-61776394-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00234 (357/152284) while in subpopulation NFE AF= 0.00394 (268/68034). AF 95% confidence interval is 0.00355. There are 1 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 13 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRIP1NM_032043.3 linkuse as main transcriptc.2097+7G>A splice_region_variant, intron_variant ENST00000259008.7 NP_114432.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRIP1ENST00000259008.7 linkuse as main transcriptc.2097+7G>A splice_region_variant, intron_variant 1 NM_032043.3 ENSP00000259008 P2Q9BX63-1

Frequencies

GnomAD3 genomes
AF:
0.00235
AC:
357
AN:
152166
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000676
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00236
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00189
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00394
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00225
AC:
566
AN:
251276
Hom.:
2
AF XY:
0.00214
AC XY:
290
AN XY:
135812
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.00202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00129
Gnomad NFE exome
AF:
0.00393
Gnomad OTH exome
AF:
0.00245
GnomAD4 exome
AF:
0.00298
AC:
4360
AN:
1461696
Hom.:
13
Cov.:
30
AF XY:
0.00284
AC XY:
2064
AN XY:
727150
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.00186
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00195
Gnomad4 NFE exome
AF:
0.00360
Gnomad4 OTH exome
AF:
0.00224
GnomAD4 genome
AF:
0.00234
AC:
357
AN:
152284
Hom.:
1
Cov.:
32
AF XY:
0.00205
AC XY:
153
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.000674
Gnomad4 AMR
AF:
0.00235
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00189
Gnomad4 NFE
AF:
0.00394
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00300
Hom.:
1
Bravo
AF:
0.00234
EpiCase
AF:
0.00344
EpiControl
AF:
0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:25
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:8
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2024BRIP1: BP4, BS2 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJun 30, 2022- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
not specified Benign:5
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 12, 2018- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 16, 2021- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMay 22, 2017- -
Benign, criteria provided, single submitterclinical testingGeneDxOct 22, 2013This 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. -
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, no assertion criteria providedclinical testingTrue Health DiagnosticsJun 18, 2018- -
Likely benign, criteria provided, single submitterclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.May 23, 2018- -
Benign, criteria provided, single submittercurationSema4, Sema4Oct 19, 2020- -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 18, 2015- -
Familial cancer of breast Uncertain:1Benign:2
Benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 01, 2023This variant is considered benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. -
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterSep 19, 2018- -
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Fanconi anemia complementation group J Benign:2
Likely benign, criteria provided, single submitterclinical testingCounsylJun 03, 2016- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioApr 25, 2023- -
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Malignant tumor of breast Benign:1
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The BRIP1 c.2097+7G>A variant was identified in 3 of 436 proband chromosomes (frequency: 0.007) from individuals or families with breast or ovarian cancer and was identified in 1 of 146 control chromosomes (frequency: 0.005) from healthy individuals (Guenard_2008, Rutter_2003, Vahteristo_2006). The variant was also identified in dbSNP (ID: rs4988352) “With Uncertain significance allele”, ClinVar (classified benign by Invitae, GeneDx, likely benign by Counsyl, Quest Diagnostics Nichols Institute San Juan Capistrano and Color Genomics Inc, and uncertain significance by Illumina), Clinvitae (6x), Zhejiang Colon Cancer Database (7x), and was not identified in Cosmic or MutDB. The variant was identified in control databases in 644 of 277018 chromosomes (2 homozygous) at a frequency of 0.002 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 8 of 24028 chromosomes (freq: 0.0003), Other in 10 of 6462 chromosomes (freq: 0.002), Latino in 72 of 34396 chromosomes (freq: 0.002), European Non-Finnish in 518 (1 homozygous) of 126558 chromosomes (freq: 0.004), European Finnish in 34 (1 homozygous) of 25788 chromosomes (freq: 0.001), and South Asian in 2 of 30780 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish and East Asian populations. 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 this variant meets our laboratory's criteria to be classified as benign. -
Ovarian neoplasm Benign:1
Likely benign, criteria provided, single submitterclinical testingCounsylJun 03, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
4.2
DANN
Benign
0.51
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000077
dbscSNV1_RF
Benign
0.0020
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4988352; hg19: chr17-59853755; API