Submissions for variant NM_032043.3(BRIP1):c.3390_3393del (p.Tyr1131fs)

dbSNP: rs778664039

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219431	SCV000273024	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-31	criteria provided, single submitter	clinical testing	The c.3390_3393delCTAT variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of 4 nucleotides at positions 3390 to 3393, causing a translational frameshift with a predicted alternate stop codon (p.Y1131Lfs*18). This alteration occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 101 amino acids of the protein. However, premature stop codons are typically deleterious in nature; however, functional and structural analyses suggest that at least two residues contained in this deleted region (Thr1133 and Lys1249) have functional importance (Leung CC et al. J Biol Chem. 2011 Feb 11;286(6):4292-301; Xie J et al. PLoS Genet. Jul 2012; 8(7): e1002786). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Illumina Laboratory Services, Illumina	RCV000396476	SCV000404574	uncertain significance	BRIP1-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	The BRIP1 c.3390_3393delCTAT (p.Tyr1131LeufsTer18) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00008 in the European (non-Finnish) population from the Exome Aggregation Consortium. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for BRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000589475	SCV000565791	likely pathogenic	not provided	2023-01-03	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 119 amino acids are lost and replaced with 17 incorrect amino acids; Not observed at a significant frequency in large population cohorts (gnomAD); Observed in an individual with prostate cancer (Hayano et al., 2016); This variant is associated with the following publications: (PMID: 22980975, 27701467, 29368626, 31685261, 30254378, 20159562, 21127055)
Invitae	RCV000543566	SCV000633669	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1131Leufs*18) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 119 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs778664039, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 27701467). This variant is also known as p.I1130fs. ClinVar contains an entry for this variant (Variation ID: 229712). This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. 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.
Counsyl	RCV000576546	SCV000677837	likely pathogenic	Fanconi anemia complementation group J; Neoplasm of ovary	2016-11-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804172	SCV000699721	likely pathogenic	Fanconi anemia complementation group J	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.3390_3393delCTAT (p.Tyr1131LeufsX18), located in the last exon, results in a premature termination codon, predicted to cause a truncation of the encoded protein. Truncations downstream of this position have not been classified as pathogenic by our laboratory but have been observed in individuals with breast and/or ovarian cancer and early-onset Prostate cancer as reported in the HGMD database. The variant allele was found at a frequency of 3.6e-05 in 250266 control chromosomes. To our knowledge, c.3390_3393delCTAT has not been reported in the literature in individuals affected with Fanconi Anemia Complementation Group J. However, c.3390_3393delCTAT has been reported in the literature in individuals affected with a variety of cancers such as Prostate (example, Hayano_2016); Breast (example, Li_2018, Vasmatzis_2020) and Pancreatic Cancer (example, Emelyanova_2022). Among these ascertained occurrences, it was reported in the germline DNA of an individual with Breast cancer (example Li_2018); as a putative germline variant due to its finding in the normal tissue of a an individual with Pancreatic Cancer (Emelyanova_2022); in settings of comprehensive genomic profiling on a liver biopsy along with other variation such as biallelic inactivation of TP53, CDH1, FOXA1, NIN and other structural rearrangements in which therapies targeting this specific mutation were invalidated over other validated therapies (Vasmatzis_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Complementation Group J. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported however another residue within this region (Threonine 1133) has been reported to be functionally relevant to BRIP1 function. The following publications have been ascertained in the context of this evaluation (PMID: 35309086, 27701467, 30385609, 31685261, 29368626). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Likely pathogenic, n=5; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic for BRIP1 associated cancer predisposition but its association with a phenotype of autosomal recessive Fanconi Anemia Complementation Group J remains uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000219431	SCV000903022	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with the last 119 amino acids of the protein replaced with 17 novel amino acids. The truncation is expected to disrupt the TopBP1 binding region and an acetylation site in the C-terminus of the BRIP1 protein, which have been reported to play an important role in DNA replication-stress response and maintaining genomic stability (PMID: 20159562, 21127055, 22792074). This variant has been reported in individuals with early-onset breast cancer (Color internal data) and in an individual affected with prostate cancer (PMID: 27701467). This variant has been identified in 9/250266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the exact mechanism by which this variant causes disease is yet to be determined, the available evidence indicates that this variant is likely to disrupt normal BRIP1 protein function. Therefore, this variant is classified as Likely Pathogenic.
Baylor Genetics	RCV003462403	SCV004214683	likely pathogenic	Familial cancer of breast	2023-10-11	criteria provided, single submitter	clinical testing
BRCAlab, Lund University	RCV003155931	SCV002588956	likely pathogenic	Ovarian cancer	2022-08-26	no assertion criteria provided	clinical testing