chr17-61801460-AT-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_032043.3(BRIP1):c.932delA(p.Tyr311PhefsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

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

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 1.40

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

familial ovarian cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Fanconi anemia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
Fanconi anemia complementation group J
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary breast carcinoma
Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
colorectal adenoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-61801460-AT-A is Pathogenic according to our data. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801460-AT-A is described in CliVar as Pathogenic. Clinvar id is 133762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3 link	c.932delA	p.Tyr311PhefsTer27	frameshift_variant	Exon 8 of 20	ENST00000259008.7	NP_114432.2	Q9BX63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 link	c.932delA	p.Tyr311PhefsTer27	frameshift_variant	Exon 8 of 20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250932

AF XY:

0.00000737

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459180

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726084

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109710

Other (OTH)

AF:

0.00

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.000207

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Mar 07, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.932delA pathogenic mutation, located in coding exon 7 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 932, causing a translational frameshift with a predicted alternate stop codon (p.Y311Ffs*27). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Jul 22, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant deletes 1 nucleotide in exon 8 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. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250932 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

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

Pathogenic:1

Feb 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 133762). This variant is present in population databases (rs587778138, ExAC 0.006%). This sequence change creates a premature translational stop signal (p.Tyr311Phefs*27) 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). -

Familial cancer of breast

Pathogenic:1

Jun 01, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over