Submissions for variant NM_032043.3(BRIP1):c.206-2A>G

gnomAD frequency: 0.00001  dbSNP: rs786203700

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167120	SCV000217950	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-18	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000214974	SCV000279366	uncertain significance	not provided	2024-02-16	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526148	SCV000633507	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-08	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000576661	SCV000677820	likely pathogenic	Fanconi anemia complementation group J; Ovarian neoplasm	2016-12-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167120	SCV000903619	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-18	criteria provided, single submitter	clinical testing	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.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310101	SCV001499633	likely pathogenic	Ovarian neoplasm	2020-04-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781516	SCV002017972	pathogenic	Fanconi anemia complementation group J	2019-03-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462235	SCV004214679	uncertain significance	Familial cancer of breast	2023-10-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000214974	SCV004704429	likely pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	BRIP1: PVS1:Strong, PM2
PreventionGenetics, part of Exact Sciences	RCV004732730	SCV005365428	likely pathogenic	BRIP1-related disorder	2024-01-08	no assertion criteria provided	clinical testing	The BRIP1 c.206-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in an individual with ovarian cancer (Norquist et al. 2016. PubMed ID: 26720728, eTable 1) and in an individual with breast cancer (Velazquez et al. 2020. PubMed ID: 32522261, Table 2). However, it has also been reported in a cancer-free individual aged at or over 40 years at the time of specimen collection (Weber-Lassalle et al. 2018. PubMed ID: 29368626, Table S2). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of uncertain significance, likely pathogenic, and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187396/). Variants that disrupt the consensus splice acceptor site in BRIP1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.