rs587780226

chr17-61799125-G-Achr17-61799125-G-Cchr17-61799125-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_032043.3(BRIP1):c.1315C>T(p.Arg439Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000411 in 1,461,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R439R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRIP1 NM_032043.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:2
• Conservation: PhyloP100: 3.69

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]

ACMG classification

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 17-61799125-G-A is Pathogenic according to our data. Variant chr17-61799125-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 128154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.1315C>T	p.Arg439Ter	stop_gained	9/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.1315C>T	p.Arg439Ter	stop_gained	9/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251156 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461288 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 06, 2023	This variant changes 1 nucleotide in exon 9 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. In a high-throughput in vitro assay, this variant failed to restore resistance to interstrand crosslink (ICL) inducing agents (PMID: 33619228). This variant has been reported in individuals affected with breast, ovarian, colon, and gastric cancer (PMID: 26681312, 26845104, 33313162, 33842585, 36627197). This variant has been identified in 3/251156 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 Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 25, 2021	The p.R439* pathogenic mutation (also known as c.1315C>T), located in coding exon 8 of the BRIP1 gene, results from a C to T substitution at nucleotide position 1315. This changes the amino acid from an arginine to a stop codon within coding exon 8. In a functional study, this alteration was found to cause cisplatin sensitivity (Calvo JA et al. Mol Cancer Res, 2021 Feb;:). This mutation has been reported in 1/384 Chinese high-risk breast cancer patients (Lang GT et al. Ann Transl Med, 2020 Nov;8:1417), in two Ashkenazi Jewish women with personal and family history of breast cancer who underwent multigene panel testing (Frey MK et al. Gynecol Oncol, 2017 07;146:123-128), in a patient diagnosed with colorectal cancer at age 45 who underwent multigene panel testing (Shirts BH et al. Genet Med, 2016 10;18:974-81), in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet Med, 2016 08;18:823-32), and in 1/13213 breast cancer cases and 0/5242 controls from the UK (Easton DF et al. J Med Genet, 2016 05;53:298-309). 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. -

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 termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 24, 2023	- -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change creates a premature translational stop signal (p.Arg439*) 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 present in population databases (rs587780226, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312, 26845104). ClinVar contains an entry for this variant (Variation ID: 128154). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

BRIP1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2023

The BRIP1 c.1315C>T variant is predicted to result in premature protein termination (p.Arg439*). This variant has been reported in individuals with breast cancer (Frey et al. 2015. PubMed ID: 26296696; Easton et al. 2016. PubMed ID: 26921362. Table S1), Seminoma (Schrader et al. 2016. PubMed ID: 26556299. Table S8), as well as colorectal cancer (Shirts et al. 2016. PubMed ID: 26845104). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59876486-G-A) and interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128154/). Nonsense variants in BRIP1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2023

Nonsense 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); Published functional studies suggest a damaging effect: failed to confer resistance to inter-strand crosslink-inducing agents (Calvo et al., 2021); This variant is associated with the following publications: (PMID: 29922827, 26556299, 26296696, 26681312, 28495237, 28849200, 26921362, 26099045, 33151324, 35273153, 26845104, 33313162, 30982232, 30850667, 36627197, 33619228, 32566746, 35053526, 33842585) -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Neoplasm of ovary;C1836860:Fanconi anemia complementation group J Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Oct 02, 2017

- -

BRIP1-Related Disorders Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 09-09-2016 by Lab Myriad Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Familial ovarian cancer Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Pathogenic and reported on 09-09-2016 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A
Vest4		0.87
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs587780226; hg19: chr17-59876486; COSMIC: COSV52002119;