NM_032043.3:c.2492+2dupT

Variant names:

• chr17-61715948-T-TA
• rs587780240
• NM_032043.3:c.2492+2dupT

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1 PP3 PP5_Very_Strong

The NM_032043.3(BRIP1):​c.2492+2dupT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,561,012 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: BRIP1 NM_032043.3 splice_donor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 8.68

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7, offset of -4, new splice context is: ttgGTaggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP3: Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
• 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 rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.2492+2dupT		splice_donor_variant, intron_variant	Intron 17 of 19	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.2492+2_2492+3insT		splice_donor_variant, intron_variant	Intron 17 of 19	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152118 Hom.: 0 Cov.: 31

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

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

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

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:10 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Feb 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 06, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 14, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2492+2dupT intronic variant, results from a duplication of two nucleotides at nucleotide position 2492 after intron 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). This alteration was also identified in an individual diagnosed with ovarian cancer (Flaum N et al. Genet Med, 2022 Dec;24:2578-2586). 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. -

Fanconi anemia complementation group J Pathogenic:2

Nov 08, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRIP1 c.2492+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 1.6e-05 in 249092 control chromosomes. c.2492+2dupT has been reported in the literature in a comppound heterozygous individual affected with Fanconi Anemia Complementation Group J or in a heterozygous individual with breast cancer (Levitus_2005, Seal_2006). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on gene expression has shown that this variant results in exon 17 or exon 18 skipping, causing a frameshift and likely nonsense-mediated decay ((Levitus_20052005). The following publications have been ascertained in the context of this evaluation (PMID: 16116423, 17033622). ClinVar contains an entry for this variant (Variation ID: 128174). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Feb 07, 2011

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

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

not provided Pathogenic:2

Jun 30, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and published studies support that this variant causes abnormal splicing, which is predicted to result in null allele (PMID: 16116423, 31642931); Observed in conjunction with another pathogenic BRIP1 variant in an individual with Fanconi anemia (PMID: 16116423); Observed in individuals with ovarian and/or breast cancer (PMID: 28888541, 17033622, 36169650, 36765687); 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, 36169650, 36765687, 31642931, 16116423) -

Sep 06, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 16116423; internal data). For these reasons, this variant has been classified as Pathogenic. -

BRIP1-related disorder Pathogenic:1

May 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial cancer of breast Pathogenic:1

Dec 08, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 “With Likely pathogenic allele”, 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

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

Other links and lift over

dbSNP: rs587780240; hg19: chr17-59793309;