Variant rs771028677 details in Genebe, Genetics Data Aggregator

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 links:

BRIP1 (HGNC:):

BRIP1 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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. Fraction of 0.203 CDS is truncated, and there are 0 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 [Likely_pathogenic]. Clinvar id is 234281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61684052-CTTTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.2990_2993delCAAA	p.Thr997fs	frameshift_variant	20/20	ENST00000259008.7	NP_114432.2	Q9BX63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.2990_2993delCAAA	p.Thr997fs	frameshift_variant	20/20	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

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250982

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135644

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 26, 2021	PVS1, PS4_Moderate, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 16, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 24, 2023	PS4_moderate, PVS1 -

Familial cancer of breast

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 01, 2023	A known pathogenic mutation was detected in the BRIPI gene (c.2990_2993delCAAA).This sequence change creates a premature translational stop signal (p.Thr997Argfs61) 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.Lys998Glufs60) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 27, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 24, 2020	- -

Hereditary cancer-predisposing syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 16, 2024	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. Premature stop codons are typically deleterious in nature, and the C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for the 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). 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 also been reported in a Japanese patient with prostate cancer (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376), a Han Chinese patient with gastric adenocarcinoma (Ji K et al. Chin J Cancer Res, 2020 Aug;32:508-515), a patient with pancreatic cancer (Hu C et al. JAMA, 2018 06;319:2401-2409), and in individuals affected with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095; AlDubayan SH et al. Am J Hum Genet, 2018 03;102:401-414). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 27, 2023	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; Ma et al, 2019; Color Health internal data), in an individual with family history of breast and ovarian cancer (PMID: 26315354; Color Health internal data), in individuals affected with colorectal cancer (PMID: 28135145, 29478780, 30675318), in an individual affected with pancreatic cancer (PMID: 32885271), in an individual affected with prostate cancer (PMID: 31214711), and 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 07, 2019	- -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 10, 2021	- -

Fanconi anemia complementation group J

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 06, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 20, 2016	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

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; Invitae). 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. -

Ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

BRCAlab, Lund University

Aug 26, 2022

- -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Sep 20, 2016

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 24, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

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

rs771028677

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over