Variant rs778664039 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_032043.3(BRIP1):c.3390_3393delCTAT(p.Tyr1131fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000149 in 1,613,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.24

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:

BRIP1 (HGNC:):

BRIP1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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 0.096 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PP5

Variant 17-61683652-AATAG-A is Pathogenic according to our data. Variant chr17-61683652-AATAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 229712.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.3390_3393delCTAT	p.Tyr1131fs	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.3390_3393delCTAT	p.Tyr1131fs	frameshift_variant	20/20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152198

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:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

250266

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135470

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.0000578

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:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1460812

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

726744

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74480

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 17, 2024	This variant deletes 4 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with the last 119 amino acids of the protein replaced with 17 novel amino acids. The truncation is expected to disrupt the TopBP1 binding region and an acetylation site in the C-terminus of the BRIP1 protein, which have been reported to play an important role in DNA replication-stress response and maintaining genomic stability (PMID: 20159562, 21127055, 22792074). This variant has been reported in individuals with early-onset breast cancer (Color internal data) and in an individual affected with prostate cancer (PMID: 27701467). This variant has been identified in 9/250266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the exact mechanism by which this variant causes disease is yet to be determined, the available evidence indicates that this variant is likely to disrupt normal BRIP1 protein function. Therefore, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 25, 2024	The c.3390_3393delCTAT variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of 4 nucleotides at positions 3390 to 3393, causing a translational frameshift with a predicted alternate stop codon (p.Y1131Lfs*18). This alteration occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 101 amino acids of the protein. However, premature stop codons are typically deleterious in nature; functional and structural analyses suggest that at least two residues contained in this deleted region (Thr1133 and Lys1249) have functional importance (Leung CC et al. J Biol Chem. 2011 Feb 11;286(6):4292-301; Xie J et al. PLoS Genet. Jul 2012; 8(7): e1002786). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change creates a premature translational stop signal (p.Tyr1131Leufs*18) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 119 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs778664039, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 27701467). This variant is also known as p.I1130fs. ClinVar contains an entry for this variant (Variation ID: 229712). This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Ovarian cancer

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

BRCAlab, Lund University

Aug 26, 2022

- -

BRIP1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 24, 2024

- -

Ovarian neoplasm;C1836860:Fanconi anemia complementation group J

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Nov 28, 2016

- -

Fanconi anemia complementation group J

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 10, 2023

Variant summary: BRIP1 c.3390_3393delCTAT (p.Tyr1131LeufsX18), located in the last exon, results in a premature termination codon, predicted to cause a truncation of the encoded protein. Truncations downstream of this position have not been classified as pathogenic by our laboratory but have been observed in individuals with breast and/or ovarian cancer and early-onset Prostate cancer as reported in the HGMD database. The variant allele was found at a frequency of 3.6e-05 in 250266 control chromosomes. To our knowledge, c.3390_3393delCTAT has not been reported in the literature in individuals affected with Fanconi Anemia Complementation Group J. However, c.3390_3393delCTAT has been reported in the literature in individuals affected with a variety of cancers such as Prostate (example, Hayano_2016); Breast (example, Li_2018, Vasmatzis_2020) and Pancreatic Cancer (example, Emelyanova_2022). Among these ascertained occurrences, it was reported in the germline DNA of an individual with Breast cancer (example Li_2018); as a putative germline variant due to its finding in the normal tissue of a an individual with Pancreatic Cancer (Emelyanova_2022); in settings of comprehensive genomic profiling on a liver biopsy along with other variation such as biallelic inactivation of TP53, CDH1, FOXA1, NIN and other structural rearrangements in which therapies targeting this specific mutation were invalidated over other validated therapies (Vasmatzis_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Complementation Group J. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported however another residue within this region (Threonine 1133) has been reported to be functionally relevant to BRIP1 function. The following publications have been ascertained in the context of this evaluation (PMID: 35309086, 27701467, 30385609, 31685261, 29368626). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Likely pathogenic, n=5; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic for BRIP1 associated cancer predisposition but its association with a phenotype of autosomal recessive Fanconi Anemia Complementation Group J remains uncertain. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2024

Frameshift variant predicted to result in abnormal protein length as the last 119 amino acids are replaced with 17 different amino acids, and other similar variants have been reported in HGMD; Observed in individuals with breast, prostate or pancreatic cancer (PMID: 27701467, 30385609, 35309086); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22980975, 27701467, 29368626, 31685261, 30254378, 20159562, 21127055, 29420467, 29922827, 35309086, 30385609) -

Familial cancer of breast

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 19, 2024

- -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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