rs587782410

chr17-61685976-A-Cchr17-61685976-A-Gchr17-61685976-A-T

Variant summary

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

The NM_032043.3(BRIP1):c.2765T>G(p.Leu922Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,916 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L922L) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 0.834

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 16 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 53 pathogenic variants in the truncated region.

PP5

Variant 17-61685976-A-C is Pathogenic according to our data. Variant chr17-61685976-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142366.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 linkuse as main transcript	c.2765T>G	p.Leu922Ter	stop_gained	19/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.2765T>G	p.Leu922Ter	stop_gained	19/20	1	NM_032043.3	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251392

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

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:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 2021	The p.L922* pathogenic mutation (also known as c.2765T>G), located in coding exon 18 of the BRIP1 gene, results from a T to G substitution at nucleotide position 2765. This changes the amino acid from a leucine to a stop codon within coding exon 18. This mutation has been identified in a cohort of unselected patients with triple negative breast cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11), in 0/3236 cases with invasive epithelial ovarian cancer and in 1/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107), 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 25, 2020	This variant changes 1 nucleotide in exon 19 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been reported in an individual affected with triple negative breast cancer (PMID: 25452441) and an unaffected control in an ovarian cancer case-control study (PMID: 26315354). This variant has been identified in 3/251392 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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Jul 29, 2022	PVS1, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 05, 2023	The BRIP1 c.2765T>G (p.Leu922*) variant causes the premature termination of BRIP1 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 25452441 (2015), 26921362 (2016), 29368626 (2018), and 33471991 (2021)), in an individual with testicular, prostate, and bladder cancer (PMDI: 35022142 (2022)), and in unaffected controls (PMIDs: 26315354 (2015), 34887416 (2021), 33804961 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ BRIP1)). The frequency of this variant in the general population, 0.000026 (3/113686 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 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); This variant is associated with the following publications: (PMID: 26315354, 25452441, 26921362, 28152038, 29368626, 29308099, 31980526, 29922827, 33804961, 35022142) -

Familial cancer of breast

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 01, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 25, 2022	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

This sequence change creates a premature translational stop signal (p.Leu922*) 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 (rs587782410, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25452441, 26921362). ClinVar contains an entry for this variant (Variation ID: 142366). For these reasons, this variant has been classified as Pathogenic. -

Neoplasm of ovary

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 02, 2016

- -

Fanconi anemia complementation group J

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 02, 2016

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Nov 25, 2016

Variant summary: The BRIP1 c.2765T>G (p.Leu922X) variant results in a premature termination codon, predicted to cause a truncated or absent BRIP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121394, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000. The variant has been reported in one triple negative breast cancer case as well as a high-risk unaffected control (Couch_2015, Ramus_2015) via publications. In addition, multiple clinical diagnostic laboratories cite the variant as "pathogenic." However, it does need to be noted, a recent publication by Easton_2016 (PMID: 26921362) indicates that the prevalence of truncating variants in BRIP1 have comparable occurrences in controls and cases, for example, p.Arg798Ter was observed in 23 cases and 18 controls, suggesting that truncating variants may not be associated with a substantial increase in breast cancer risk, although the authors do state "BRIP1 screening might have utility for ovarian cancer risk prediction, in combination with other risk factors." Therefore, the variant of interest has been classified as "Likely Pathogenic." -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.28

Cadd

Pathogenic

Dann

Uncertain

0.98

Eigen

Uncertain

0.40

Eigen_PC

Benign

0.092

FATHMM_MKL

Benign

0.088

MutationTaster

Benign

1.0

A;D

Vest4

0.90

GERP RS

4.7

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

Other links and lift over