rs771028677

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_032043.3(BRIP1):c.2990_2993delCAAA(p.Thr997ArgfsTer61) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,572 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T997T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:26U:2

Conservation

PhyloP100: 0.735

Publications

12 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_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 59 pathogenic variants in the truncated region.

PP5

Variant 17-61684052-CTTTG-C is Pathogenic according to our data. Variant chr17-61684052-CTTTG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 234281.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3 link	c.2990_2993delCAAA	p.Thr997ArgfsTer61	frameshift_variant	Exon 20 of 20	ENST00000259008.7	NP_114432.2	Q9BX63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 link	c.2990_2993delCAAA	p.Thr997ArgfsTer61	frameshift_variant	Exon 20 of 20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

250982

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461458

Hom.:

AF XY:

0.0000330

AC XY:

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33402

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86168

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000405

AC:

AN:

1111872

Other (OTH)

AF:

0.0000497

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.0000263

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:26Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:8Uncertain:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BRIP1: PVS1:Strong, PS4:Moderate, PM2:Supporting -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 26, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS4_Moderate, PM2 -

Mar 25, 2025

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been identified by standard clinical testing. Female patient with ovarian cancer Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1 -

Jul 31, 2024

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRIP1 c.2990_2993del (p.Thr997Argfs*61) variant alters the translational reading frame of the BRIP1 mRNA and causes the premature termination of BRIP1 protein synthesis. This variant has been reported in the published literature in individuals with ovarian cancer (PMID: 26315354 (2015)), breast cancer (PMID: 26786923 (2016), 26921362 (2016), 36551643 (2022)), colorectal cancer (PMID: 28135145 (2017), 29478780 (2018)), pancreatic cancer (PMID: 29922827 (2018), 32885271 (2021)), a Lynch syndrome-associated cancer (PMID: 30254378 (2019)), prostate cancer (PMID: 31214711 (2020)), and gastric adenocarcinoma (PMID: 32963463 (2020)). This variant is also reported in unaffected individuals (PMID: 26786923 (2016), 26921362 (2016), 30254378 (2019)). Based on the available information, this variant is classified as pathogenic. -

Jan 24, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4_moderate, PVS1 -

Aug 06, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation, as the last 253 amino acids are replaced with 60 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Disrupts a critical functional domain: BRCA1 binding domain and TOPBP1 interaction domain (PMID: 11301010, 20159562, 21127055); Observed in individuals with a personal or family history of breast, ovarian, and other cancers (PMID: 26315354, 26921362, 26786923, 28135145, 28888541, 32963463, 32885271); This variant is associated with the following publications: (PMID: 26786923, 30675318, 26315354, 26921362, 18628483, 29478780, 28135145, 31214711, 32963463, 29922827, 28888541, 32885271, 34697415, 33804961, MilanoL2023[preprint], 34308104, 35273153, 35753512, 29368626, 30254378, 32676327, 32191290, 34887416, 11301010, 20159562, 21127055, 35534704, 35980532) -

Familial cancer of breast

Pathogenic:5

Feb 27, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Nov 24, 2020

Genetics and Molecular Pathology, SA Pathology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A known pathogenic mutation was detected in the BRIPI gene (c.2990_2993delCAAA).This sequence change creates a premature translational stop signal (p.Thr997Argfs*61) in the BRIPI gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 253 amino acid(s) of the BRIPI protein. This variant is present in population databases (rs771028677, gnomAD 0.006%). It has been reported in the literature in individuals affected with Breast and Ovarian, Pancreatic and Prostate Cancer (Thompson 2016, Ramus 2015, Easton 2016, Lerner-ElIis_202I, Nguyen-Dumont_2021). ClinVar contains an entry for this variant (Variation ID: 234281). This variant disrupts a region of the BRIPI protein in which other variant(s) (p.Lys998Glufs*60) have been determined to be pathogenic (PMID: 18628483). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be diseasecausing. For these reasons, this variant has been classified as Pathogenic. -

Aug 01, 2022

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia complementation group J

Pathogenic:4

Dec 06, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 02, 2018

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 18, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRIP1 c.2990_2993del (p.Thr997ArgfsTer61) change deletes four nucleotides to cause a frameshift and the creation of a premature stop codon. This variant is not predicted to result in nonsense mediated decay, however the truncated region is critical to protein function. This variant has been reported in individuals with a personal and/or family history of ovarian and breast cancer (PMID: 26315354, 26921362). In summary, this variant meets criteria to be classified as likely pathogenic.? -

Hereditary cancer-predisposing syndrome

Pathogenic:3Uncertain:1

Feb 10, 2021

Sema4, Sema4

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jun 07, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant deletes 4 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the functional domains involved in BRCA1-binding, DNA damage and replication stress responses and attenuation of DNA damage tolerance pathway (PMID: 11301010, 14983014, 20159562, 20173781, 22792074). Although functional studies have not been reported for this variant, it is expected to impair BRIP1 protein function. This variant has been reported in individuals affected with breast cancer (PMID: 26921362, 36551643, 38003901; Ma et al, 2019; DOI: 10.1101/2023.07.03.23290133), ovarian cancer (DOI: 10.1101/2023.07.03.23290133), family history of breast and ovarian cancer (PMID: 26315354), colorectal cancer (PMID: 28135145, 29478780, 30675318), pancreatic cancer (PMID: 32885271), prostate cancer (PMID: 31214711), as well as in individuals unaffected with breast cancer (PMID: 26921362, 30254378). This variant has been identified in 8/250982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 13, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2990_2993delCAAA pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from a deletion of four nucleotides between nucleotide positions 2990 and 2993, causing a translational frameshift with a predicted alternate stop codon (p.T997Rfs*61). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 253 amino acids of the protein. The exact functional effect of this alteration is unknown. While the C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for some aspects of BRIP1 protein function (Gong Z et al. Mol. Cell, 2010 Feb;37:438-46; Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301; Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786), functional studies have shown that truncations in the 3' terminus of BRIP1 are functional in response to intra-strand cross-linking agents (Calvo JA et al. Mol Cancer Res, 2021 Jun;19:1015-1025). This deletion has been identified in patients with a personal or family history of breast and/or ovarian cancer (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107; Easton DF et al. J Med Genet, 2016 05;53:298-309; Thompson ER et al. J Clin Oncol, 2016 May;34:1455-9) and has also been identified in controls or healthy individuals (Easton DF et al. J Med Genet, 2016 05;53:298-309; Thompson ER et al. J Clin Oncol, 2016 May;34:1455-9; Rowley SM et al. Genet Med, 2019 04;21:913-922). This variant has been detected in the homozygous state in individuals with no reported features of BRIP1-related Fanconi Anemia (FA-J) (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear. -

Ovarian cancer

Pathogenic:2

Aug 26, 2022

BRCAlab, Lund University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 20, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Oct 08, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 24, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRIP1 c.2990_2993delCAAA (p.Thr997ArgfsX61) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.9e-05 in 254976 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome (3.9e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.2990_2993delCAAA has been reported in the literature in individuals affected with Breast and Ovarian, Pancreatic and Prostate Cancer (Thompson 2016, Ramus 2015, Easton 2016, Lerner-Ellis_2021, Nguyen-Dumont_2021). These data indicate that the variant is very likely to be associated with disease. 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Thr997Argfs*61) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 253 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs771028677, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with a family history of breast and ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 234281). This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Lys998Glufs*60) have been determined to be pathogenic (PMID: 18628483; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Familial ovarian cancer

Pathogenic:1

Mar 13, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.73

Mutation Taster

=14/186

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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