Submissions for variant NM_032043.3(BRIP1):c.3730_3731del (p.Met1244fs)

gnomAD frequency: 0.00003  dbSNP: rs730881646

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160359	SCV000210865	uncertain significance	not provided	2023-08-04	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation as the last 6 amino acids are lost and replaced with 4 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Observed in an individuals with kidney cancer and prostate cancer (Beebe-Dimmer et al., 2018; Huang et al., 2018); This variant is associated with the following publications: (PMID: 29356034, 26689913, 29625052, 22792074)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205061	SCV000260036	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met1244Valfs*5) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs730881646, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with prostate or renal cancer (PMID: 29356034, 29625052, 36451132). ClinVar contains an entry for this variant (Variation ID: 182368). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Ambry Genetics	RCV000217493	SCV000276075	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-28	criteria provided, single submitter	clinical testing	The c.3730_3731delAT variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of two nucleotides at nucleotide positions 3730 to 3731, causing a translational frameshift with a predicted alternate stop codon (p.M1244Vfs*5). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 6 amino acids of the protein. The exact functional effect of this alteration is unknown, however, functional studies suggest that at least one residue contained in this deleted region (Lys1249) has functional importance (Xie J et al. PLoS Genet. Jul 2012; 8(7): e1002786). This alteration has been reported in multiple individuals diagnosed with prostate cancer (Beebe-Dimmer JL et al Prostate. 2018 04;78(5):321-326; Manneh R et al. JCO Precis Oncol, 2024 May;8:e2300628). This alteration was also reported in an individual with clear cell renal carcinoma (Huang KL et al. Cell, 2018 04;173:355-370.e14). Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000205061	SCV002776216	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-02-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462086	SCV004214734	uncertain significance	Familial cancer of breast	2024-01-06	criteria provided, single submitter	clinical testing