chr17-61686166-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_032043.3(BRIP1):​c.2576-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 splice_acceptor, intron

Scores

3
2
2
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.52

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.088 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of 1, new splice context is: ggtttacctttttctttaAGact. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PP5
Variant 17-61686166-C-T is Pathogenic according to our data. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686166-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 142551.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
BRIP1NM_032043.3 linkc.2576-1G>A splice_acceptor_variant, intron_variant Intron 18 of 19 ENST00000259008.7 NP_114432.2 Q9BX63-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRIP1ENST00000259008.7 linkc.2576-1G>A splice_acceptor_variant, intron_variant Intron 18 of 19 1 NM_032043.3 ENSP00000259008.2 Q9BX63-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461676
Hom.:
0
Cov.:
34
AF XY:
0.00000550
AC XY:
4
AN XY:
727154
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39682
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86236
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000108
AC:
12
AN:
1111874
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000429
Hom.:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:2
Apr 16, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. This sequence change affects an acceptor splice site in intron 18 of the BRIP1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 142551). Studies have shown that disruption of this splice site results in skipping of exon 19, but is expected to preserve the integrity of the reading-frame (Invitae). -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2
Sep 16, 2024
Color Diagnostics, LLC DBA Color Health
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant causes a G to A nucleotide substitution at the -1 position of intron 18 of the BRIP1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing, potentially by creating a de novo splice acceptor site 1 basepair upstream and resulting in a stop codon 3 codons downstream. In addition, unpublished RNA studies have been reported that this variant likely results in a truncated protein product (ClinVar Variation ID: 142551). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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 Likely Pathogenic. -

May 09, 2024
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2576-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 18 of the BRIP1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Familial cancer of breast Pathogenic:1
May 25, 2023
Myriad Genetics, Inc.
Significance:Likely pathogenic
Review Status:flagged submission
Collection Method:clinical testing

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
34
DANN
Benign
0.97
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.90
D
PhyloP100
3.5
GERP RS
4.0
Mutation Taster
=3/97
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.92
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.63
Position offset: -2
DS_AL_spliceai
0.99
Position offset: -1

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

Publications

Other links and lift over

dbSNP: rs587782539; hg19: chr17-59763527; API