rs786203700

Positions:

chr17-61857233-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePP3_StrongPP5

The NM_032043.3(BRIP1):c.206-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000807 in 1,611,772 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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:5

Conservation

PhyloP100: 4.33

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 Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.046133332 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of -33, new splice context is: attgatgtttatttaattAGata. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-61857233-T-C is Pathogenic according to our data. Variant chr17-61857233-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187396.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=3, Pathogenic=1}. Variant chr17-61857233-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.206-2A>G		splice_acceptor_variant		ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.206-2A>G		splice_acceptor_variant		1	NM_032043.3	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250636

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135608

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1459600

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726234

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant demonstrated to result in abnormal splicing; however, the effect on protein function is unknown (External communication with Ambry Genetics and Invitae); Observed in individuals with breast, ovarian, or other cancer, but also in unaffected controls (PMID: 26720728, 29368626, 32522261, 35988656); This variant is associated with the following publications: (PMID: 26720728, 31589614, 35988656, 32522261, 29368626) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	BRIP1: PVS1:Strong, PM2 -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 18, 2023	This variant causes an A to G nucleotide substitution at the canonical -2 position of intron 3 splice acceptor site of the BRIP1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study at an external laboratory has shown that this variant results in abnormal splicing in clinical samples tested and is expected to result in an absent or non-functional protein product (ClinVar SCV000217950.5). A subsequent RNA study has shown that this variant results in transcripts with an in-frame deletion of 3 or 4 amino acids, and functional consequence of these alternate transcripts is not clear (ClinVar SCV000217950.5). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 26720728, 29368626; Color internal data) and in an unaffected individual (PMID: 32522261). This variant has been identified in 1/250636 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the contradictory RNA study results, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 18, 2023	The c.206-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 3 in the BRIP1 gene. In one study of 1915 women with ovarian cancer, who were unselected for age at diagnosis or family history, this variant was reported in a patient with serous ovarian cancer diagnosed at age 61 (Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90).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. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to proteins with an in-frame deletion of 3 amino acids and 4 amino acids; however, the exact functional impact of the deleted amino acids are unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ovarian neoplasm;C1836860:Fanconi anemia complementation group J

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Dec 22, 2016

- -

Fanconi anemia complementation group J

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 09, 2019

- -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Apr 02, 2020

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2023

This sequence change affects an acceptor splice site in intron 3 of the BRIP1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in two alternative in-frame transcripts. These alternative transcripts, one with a loss of 3 amino acid residues and the other with a loss of 4 amino acid residues, are expected to preserve the integrity of the reading-frame and as such, their functional consequence cannot be determined. This variant is present in population databases (rs786203700, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with ovarian cancer and breast cancer (PMID: 26720728, 32522261). ClinVar contains an entry for this variant (Variation ID: 187396). Studies have shown that disruption of this splice site results in the activation of two different cryptic splice sites in exon 4, but the impact on the resulting protein products is unknown (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Benign

0.96

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.88

MutationTaster

Benign

1.0

D;D

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.90

Position offset: -11

DS_AL_spliceai

0.99

Position offset: -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