Variant chr17-61776458-C-CAA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The ENST00000259008.7(BRIP1):c.2039_2040insTT(p.Leu680PhefsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L680L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

BRIP1
ENST00000259008.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 8.40

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-61776458-C-CAA is Pathogenic according to our data. Variant chr17-61776458-C-CAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.2039_2040insTT	p.Leu680PhefsTer9	frameshift_variant	14/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.2039_2040insTT	p.Leu680PhefsTer9	frameshift_variant	14/20	1	NM_032043.3	ENSP00000259008	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000126

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 29, 2017	This frameshift variant causes the premature termination of BRIP1 protein synthesis. In addition, it has been reported in individuals with breast and/or ovarian cancer in the published literature (PMID: 25452441 (2015), 26681312 (2015), 26315354 (2015), and 26845104 (2016)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25452441, 26921362, 26315354, 26681312, 28152038, 24728327, 26845104, 21964575, 17033622, 32427313, 16116423, 32295079, 33471991, 30254378, 25807282, 33858029, 28888541) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Nov 28, 2022	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2023	This variant inserts 2 nucleotides in exon 14 of the BRIP1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 25452441, 26315354, 26681312, 26845104, 26921362, 33471991) as well as in unaffected individuals (PMID: 30254378, 33471991). This variant has not been identified 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 Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 03, 2021	The c.2038_2039dupTT pathogenic mutation, located in coding exon 13 of the BRIP1 gene, results from a duplication of TT at nucleotide position 2038, causing a translational frameshift with a predicted alternate stop codon (p.L680Ffs*9). This mutation has been reported in multiple breast and/or ovarian cancer patients (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Shirts BH et al. Genet Med, 2016 10;18:974-81; Easton DF et al. J Med Genet, 2016 05;53:298-309; Susswein LR et al. Genet Med, 2016 08;18:823-32; Dorling et al. N Engl J Med. 2021 02;384:428-439), and has also been detected in healthy individuals undergoing multigene panel testing (Sulem P et al. Nat Genet, 2015 May;47:448-52; Rowley SM et al. Genet Med, 2019 04;21:913-922; Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -

Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 15, 2024	- -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

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 08, 2024

This sequence change creates a premature translational stop signal (p.Leu680Phefs*9) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 21964575, 25452441, 26315354, 26681312, 26845104). This variant is also known as c.2040_ 2041insTT. ClinVar contains an entry for this variant (Variation ID: 128166). For these reasons, this variant has been classified as Pathogenic. -

Fanconi anemia complementation group J

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 10, 2016

- -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 10, 2016

- -

Uterine corpus cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Feb 21, 2023

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

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