Submissions for variant NM_032043.3(BRIP1):c.3209C>A (p.Ser1070Ter)

dbSNP: rs777213170

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459986	SCV000547352	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-06-07	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 407856). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1070*) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 180 amino acid(s) of the BRIP1 protein.
GeneDx	RCV000481412	SCV000572718	uncertain significance	not provided	2024-11-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation as the last 180 amino acid(s) are lost; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25846551, 20159562, 21127055)
Ambry Genetics	RCV002323711	SCV002609359	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-10-20	criteria provided, single submitter	clinical testing	The p.S1070* variant (also known as c.3209C>A) located in coding exon 19 of the BRIP1 gene, results from a C to A substitution at nucleotide position 3209. This changes the amino acid from a serine to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of BRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 180 amino acids of the protein. Premature stop codons are typically deleterious in nature and the impacted C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for the protein function (Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301. Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786; Gong Z et al. Mol. Cell, 2010 Feb;37:438-46). Based on the majority of available evidence to date, this variant is likely to be pathogenic
Baylor Genetics	RCV003463899	SCV004217143	likely pathogenic	Familial cancer of breast	2023-02-23	criteria provided, single submitter	clinical testing