Submissions for variant NM_032043.3(BRIP1):c.3651G>A (p.Trp1217Ter)

gnomAD frequency: 0.00003  dbSNP: rs542698396

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166368	SCV000217158	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	The p.W1217* variant (also known as c.3651G>A) located in coding exon 19 of the BRIP1 gene, results from a G to A substitution at nucleotide position 3651. This changes the amino acid from a tryptophan to a stop codon within coding exon 19. In one case-control study, this alteration was identified in 0/13213 breast cancer cases and in 1/5242 controls from the United Kingdom (Easton DF et al. J. Med. Genet. 2016 May;53:298-309). Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 33 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural and functional studies suggest that at least two residues contained in this deleted region (Ser1237 and Lys1249) have functional importance (Olsen JV et al. Sci Signal. 2010 Jan;3:ra3; Xie J et al. PLoS Genet. 2012 Ju;8:e1002786). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457986	SCV000547254	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1217*) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs542698396, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 186726). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222418	SCV000699725	uncertain significance	not specified	2022-03-29	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.3651G>A (p.Trp1217X) located in the last exon results in a premature termination codon, predicted to cause a truncation of the last 33 amino acids of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory. The variant allele was found at a frequency of 1.9e-05 in 261294 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3651G>A has been reported in the literature as a germline VUS variant in cases of men with aggressive prostate cancer undergoing multigene panel testing (example, Nguyen-Dumont_2021), in settings of multigene panel testing in a case of chronic eosinophlic leukemia with novel t(5;12) (q23;31;p13)/ETV6-ACSL6 gene fusion, in which patient was resistant to TKI therapy (example, Su_2016), in a glioblastoma tumor type within The Cancer Genome Atlas (TGCA) collection (example, Lu_2015), in control cohorts from the ExAC database (example, Weber-Lassalle_2018), and an other UK control cohort (example, Easton_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000586366	SCV000779489	uncertain significance	not provided	2023-12-14	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation as the last 33 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27458550, 26689913, 33804961, 26921362, 29368626)
Counsyl	RCV000662837	SCV000785695	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2017-11-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166368	SCV000912101	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 20 of the BRIP1 gene, creating a 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/282186 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002222418	SCV004026869	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462213	SCV004217040	uncertain significance	Familial cancer of breast	2024-02-07	criteria provided, single submitter	clinical testing