rs200050729

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_032043.3(BRIP1):c.380-17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,602,000 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: 0.0940

Publications

1 publications found

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]

BRIP1 Gene-Disease associations (from GenCC):

familial ovarian cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Fanconi anemia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
Fanconi anemia complementation group J
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary breast carcinoma
Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
colorectal adenoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 17-61849273-A-T is Benign according to our data. Variant chr17-61849273-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136577.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3 link	c.380-17T>A		intron_variant	Intron 4 of 19	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 link	c.380-17T>A		intron_variant	Intron 4 of 19	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes

AF:

0.000356

AC:

AN:

151862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000986

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00105

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000280

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000406

AC:

AN:

241600

AF XY:

0.000359

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000851

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.000472

Gnomad NFE exome

AF:

0.000370

Gnomad OTH exome

AF:

0.000511

GnomAD4 exome

AF:

0.000279

AC:

405

AN:

1450020

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

195

AN XY:

721316

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

32952

American (AMR)

AF:

0.00103

AC:

AN:

43510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25858

East Asian (EAS)

AF:

0.0000759

AC:

AN:

39502

South Asian (SAS)

AF:

0.000416

AC:

AN:

84044

European-Finnish (FIN)

AF:

0.000510

AC:

AN:

52954

Middle Eastern (MID)

AF:

0.000185

AC:

AN:

5400

European-Non Finnish (NFE)

AF:

0.000244

AC:

270

AN:

1105904

Other (OTH)

AF:

0.000334

AC:

AN:

59896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000355

AC:

AN:

151980

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41508

American (AMR)

AF:

0.000985

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00105

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000280

AC:

AN:

67918

Other (OTH)

AF:

0.000476

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.000370

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 24, 2017

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Oct 01, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1_Supporting (RNA) BRIP1 c.380-17T>A is an intronic variant located close to a canonical splice site. This variant is found in 103/258690 alleles at a frequency of 0.039% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts that the variant impairs the splicing acceptor site of exon 5 (delta score = 0.24). An internal RNA assay with primers annealing exons 3 and 6 in cultured lymphocytes from a carrier patient in the presence of NMD-inhibition was performed. It showed that this variant abolishes the natural donor splice site of exon 5, causing the skipping of this exon (r.380_507del), which is predicted to lead to a truncated protein triggering NMD (p.Ser128*). This transcript was also detected in controls, although at a lower proportion compared to the patient sample. Quantification of transcript proportions using a tag-SNP could not be performed (PVS1_Supporting (RNA), unpublished data). It has been reported in the ClinVar database (1x Uncertain Significance; 9x Likely benign; 1x Benign) and in the LOVD database (4 likely benign) with conflicting interpretations of pathogenicity. Based on currently available information, the variant c.380-17T>A should be considered an uncertain significance variant. -

Jun 05, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jul 22, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jan 14, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Jun 05, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.6

(source)

DANN

Benign

0.38

PhyloP100

0.094

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: -17

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over