Variant rs587780240 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

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

PP5

Variant 17-61715948-T-TA is Pathogenic according to our data. Variant chr17-61715948-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128174.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.2492+2_2492+3insT		splice_region_variant, intron_variant		ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.2492+2_2492+3insT		splice_region_variant, intron_variant		1	NM_032043.3	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

4

AN:

152118

Hom.:

0

Cov.:

31

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

4

AN:

249092

Hom.:

0

AF XY:

0.0000223

AC XY:

3

AN XY:

134772

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:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000220

AC:

31

AN:

1408894

Hom.:

0

Cov.:

27

AF XY:

0.0000156

AC XY:

11

AN XY:

703616

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:

0.0000281

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000263

AC:

4

AN:

152118

Hom.:

0

Cov.:

31

AF XY:

0.0000135

AC XY:

1

AN XY:

74324

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 06, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 29, 2023	The c.2492+2dupT intronic variant results from a duplication of T two nucleotides after coding exon 16 of the BRIP1 gene. In one study, this alteration was detected in conjunction with a BRIP1 nonsense mutation in an individual with Fanconi Anemia type J. Sequencing of cDNA from this individual showed three species of BRIP1 mRNA, two of which lacked either exon 17 or 18, both leading to a frameshift with a resultant truncated protein. Western blot of BRIP1 in this patient cell line did not detect full length protein indicating that the patient had two null alleles (Levitus M et al. Nat. Genet. 2005 Sep; 37(9):934-5). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 07, 2023	This variant inserts one nucleotide at the +3 position of intron 17 of the BRIP1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported that this variant leads to the skipping of exon 17 or 18 in the RNA transcript (PMID: 16116423). The aberrant transcripts are predicted to create a frameshift and premature translation stop signal and to result in an absent or non-functional protein product. This variant and another pathogenic BRIP1 variant have been reported in an individual affected with Fanconi anemia (PMID: 16116423). Cells derived from this individual showed no detectable BRIP1 protein expression. This variant has been reported in an individual affected with ovarian cancer (PMID: 30322717), as well as in an individual affected with familial breast cancer without clear segregation of the variant with disease in the family (PMID: 17033622). This variant has been identified in 5/280456 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 Likely Pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2022	Intronic splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Published studies support that this variant causes abnormal splicing, which is predicted to result in null allele (Levitus et al., 2005; Karam et al., 2019); Observed in conjunction with another pathogenic BRIP1 variant in an individual with Fanconi anemia (Levitus et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19763819, 17033622, 26709662, 20346647, 26681312, 19339519, 15285897, 30322717, 28888541, 25583207, 32359370, 31341520, 16116423, 31642931) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 06, 2023	The BRIP1 c.2492+2dup variant disrupts a canonical splice-donor site and interferes with normal BRIP1 mRNA splicing. This variant has been reported in the published literature in individuals with ovarian cancer (PMID: 30322717 (2018)) and breast cancer (PMID: 17033622 (2006)). This variant has also been seen in combination with another pathogenic BRIP1 variant in an individual with autosomal recessive Fanconi anemia (PMID: 16116423 (2005)). Experimental studies report this variant results in the skipping of exon 17 or 18 (PMIDs: 31642931 (2019), 16116423 (2005)). The frequency of this variant in the general population, 0.000039 (5/128220 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change falls in intron 17 of the BRIP1 gene. It does not directly change the encoded amino acid sequence of the BRIP1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587780240, gnomAD 0.004%). This variant has been observed in individual(s) with ovarian cancer, breast cancer and Fanconi anemia (PMID: 16116423, 17033622, 30322717). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 128174). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 17 and introduces a premature termination codon (PMID: 16116423; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

BRIP1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2023

The BRIP1 c.2492+2dupT variant is predicted to result in an intronic duplication. **Use instead**, which is predicted to interfere with splicing (Alamut Visual Plus v.1.6.1). This variant, also known as IVS17+2insT, was reported in the compound heterozygous state in an individual with Fanconi anemia (Table 1, Levitus M et al. 2005. PubMed ID: 16116423). This variant has also been reported in the heterozygous state in individuals with breast cancer and ovarian cancer (Table 1, Seal S et al 2006. PubMed ID: 17033622; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table S7, Lilyquist J et al. 2017. PubMed ID: 28888541). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59793309-T-TA). This variant is interpreted as likely pathogenic. -

Fanconi anemia complementation group J

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Leiden Open Variation Database

Feb 07, 2011

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 06, 2023

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRIP1 c.2492+2dup variant was identified in 3 of 22886 proband chromosomes (frequency: 0.0001) from individuals or families with Fanconi anemia, breast cancer and unspecified cancer (Susswein 2016, Levitus 2005, Seal 2006). The variant was also identified in dbSBP (ID: rs587780240) as â€šÃ„ÃºWith Likely pathogenic alleleâ€šÃ„Ã¹, and the ClinVar and Clinvitae datbases (3x likely pathogenic: GeneDx, Ambry Genetics, Invitae). The variant was not identified in COSMIC, MutDB, or the Zhejiang Colon Cancer databases. The variant was identified in control databases in 5 of 275052 chromosomes from European non-Finnish individuals at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). This variant has been observed in an individual with Fanconi Anemia where sequencing of cDNA identified three different species of FANCJ mRNA, two of which lacked either exon 17 or 18, both leading to a frameshift resulting in partial deletion of helicase motif VI. However, the individual with this variant also had the recurrent nonsense mutation R798X in exon 17, which predicts a truncated protein in which the helicase motif VI and the BRCA1- interacting region are deleted (Levitus 2005). In a UK study of 1212 familial breast cancer patients and 2081 healthy controls this variant was identified in one individual with breast cancer but co-segregation was not observed in the family (Seal 2006). The patient's sister and two cousins with breast cancer were BRIP1 wild type. Patient's mother and one other sister also having breast cancer were not tested. Age of onset for patient (54yo) did not differ significantly from other family members with breast cancer (range 43-60yo). The variant was also identified in one individual from 10,030 American consecutive hereditary cancer patients tested by an NGS hereditary cancer panel (Susswein 2016). The authors predict that the variant is expected to be pathogenic based on splicing predictions, however the individual with the variant had no clinical history of cancer. The c.2492+2dup variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: 3

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.

rs587780240

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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