Submissions for variant NM_032043.3(BRIP1):c.3411_3420del (p.Leu1136_Tyr1137insTer)

dbSNP: rs876660100

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213148	SCV000277242	likely pathogenic	Hereditary cancer-predisposing syndrome	2017-09-07	criteria provided, single submitter	clinical testing	The c.3411_3420del10 variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of 10 nucleotides between nucleotide positions 3411 and 3420, causing a translational frameshift with a predicted alternate stop codon. Frameshifts are typically deleterious in nature, however, this deletion and subsequent frameshift occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense mediated decay (NMD), and results in the removal of only the last 112 amino acids of the protein. 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(104):ra3; 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175603	SCV001339254	uncertain significance	not specified	2020-03-06	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.3411_3420del10 (p.Tyr1137X) results in a premature termination codon, predicted to cause a truncation of the encoded protein but not expected to result in nonsense mediated decay. The variant was absent in 249576 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3411_3420del10 in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. The variant resides in a region that has been shown to affect binding of TopBP1 a protein that plays an important role in the control of DNA replication checkpoint (PMID: 20159562). However, functional significance of this interaction is limited. One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS- possibly pathogenic until additional clinical and functional evidence is obtained.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853608	SCV002154409	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-04-03	criteria provided, single submitter	clinical testing	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 232964). 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.Tyr1137*) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 113 amino acid(s) of the BRIP1 protein.