Variant rs763443434 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_032043.3(BRIP1):c.3004_3005insTGACAGCT(p.Trp1002LeufsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.07

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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 0.199 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-61684041-C-CAGCTGTCA is Pathogenic according to our data. Variant chr17-61684041-C-CAGCTGTCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186335.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.3004_3005insTGACAGCT	p.Trp1002LeufsTer60	frameshift_variant	20/20	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.3004_3005insTGACAGCT	p.Trp1002LeufsTer60	frameshift_variant	20/20	1	NM_032043.3	ENSP00000259008	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251210

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 07, 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	Baylor Genetics	Sep 12, 2023	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 20, 2022

This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Asn1006*) have been determined to be pathogenic (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. ClinVar contains an entry for this variant (Variation ID: 186335). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is present in population databases (rs763443434, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Trp1002Leufs*60) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 248 amino acid(s) of the BRIP1 protein. -

BRIP1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2024

The BRIP1 c.3004_3005insTGACAGCT variant is predicted to result in a frameshift and premature protein termination (p.Trp1002Leufs*60). This frameshift variant is located in the last exon of BRIP1; thus this variant is not expected to result in nonsense-mediated mRNA decay. However loss of function variants downstream of this variant have been reported in BRIP1 associated disorders indicating the truncated region is important (example, Ramus. 2015. PubMed ID: 26315354). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186335/). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 27, 2017

This frameshift variant alters the translational reading frame of the BRIP1 mRNA and causes the premature termination of BRIP1 protein synthesis. The variant has not been reported in the published literature. However, a different, but related frameshift variant was identified in a family affected with breast cancer and it was shown to be unstable (PMID: 18628483 (2008)). The frequency of the c.3004_3005insTGACAGCT variant in the general population, 0.0000071 (2/282596 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2021

The c.3004_3005insTGACAGCT pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from an insertion of 8 nucleotides at position 3004, causing a translational frameshift with a predicted alternate stop codon (p.W1002Lfs*60). Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 248 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, the C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for the protein function (Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301. Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786; Gong Z et al. Mol. Cell, 2010 Feb;37:438-46). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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