Submissions for variant NM_032043.3(BRIP1):c.3401del (p.Pro1134fs)

dbSNP: rs756853672

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205001	SCV000261834	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro1134Leufs*16) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 116 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs756853672, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast, ovarian and/or renal cancer and unaffected control individuals (PMID: 16280053, 20616022, 26315354, 26921362, 35441217). ClinVar contains an entry for this variant (Variation ID: 220899). 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.
GeneDx	RCV000732737	SCV000279479	likely pathogenic	not provided	2020-11-13	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation as the last 116 amino acids are lost and replaced with 15 incorrect amino acids, disrupting the critical TOPBP1 interaction domain (Gong 2010, Leung 2011); Observed in individuals with a personal history of breast or ovarian cancer (Lewis 2005, Walsh 2010, Easton 2016); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26315354, 20616022, 16280053, 26921362, 29922827, 19763819)
Eurofins Ntd Llc (ga)	RCV000732737	SCV000860721	uncertain significance	not provided	2018-04-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000772027	SCV000904989	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last coding exon. The mutant transcript is expected to escape nonsense-mediated decay and expressed as a truncated protein that lacks the last 100 amino acids of the protein. The truncated protein is expected to disrupt the TopBP1 binding domain (a.a. 1106-1178) and acetylation site (p.Lys1249) in the C-terminus, 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 breast or ovarian cancer (PMID: 16280053, 20616022), renal cell carcinoma (PMID: 35441217), and in an unaffected control subject (PMID: 26315354). This variant has been identified in 3/250050 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.
Ambry Genetics	RCV000772027	SCV001181660	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-10	criteria provided, single submitter	clinical testing	The c.3401delC variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 3401, causing a translational frameshift with a predicted alternate stop codon (p.P1134Lfs*16). This alteration has been reported in individuals with breast and/or ovarian cancer and well as an individual with renal cell carcinoma (Lewis AG et al. Breast Cancer Res. 2005 Oct;7(6):R1005-16; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Jul;107(28):12629-33; Easton DF et al. J Med Genet, 2016 May;53:298-309; Yngvadottir B et al. Hum Mol Genet, 2022 Aug;31:3001-3011). One computational model showed no significant effect on mRNA structure as a result of this variant (Lewis AG et al. Breast Cancer Res. 2005 Oct;7(6):R1005-16). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 100 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003462392	SCV004217104	likely pathogenic	Familial cancer of breast	2023-05-30	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786553	SCV005398624	uncertain significance	Fanconi anemia complementation group J	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Fanconi anemia, complementation group J (MIM#609054). This gene is also implicated in susceptibility to early-onset breast cancer (MIM#114480). (I) 0108 - This gene is associated with both recessive and dominant disease. Fanconi anemia, complementation group J is inherited in an autosomal recessive pattern, while susceptibility to breast cancer follows an autosomal dominant inheritance pattern (OMIM). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Another truncating variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. A truncating variant downstream of this one has been described as both likely pathogenic and VUS in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been described as likely pathogenic and VUS in ClinVar. This variant has also been identified in both case and control individuals in inherited cancer cohorts (PMID: 16280053; 26921362). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign