chr17-61683314-CAT-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate
The NM_032043.3(BRIP1):c.3730_3731delAT(p.Met1244ValfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,609,598 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_032043.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152144Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250414Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135302
GnomAD4 exome AF: 0.00000549 AC: 8AN: 1457454Hom.: 0 AF XY: 0.00000414 AC XY: 3AN XY: 725302
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152144Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:2
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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 (internal data). 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. -
not provided Uncertain:1
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) -
Hereditary cancer-predisposing syndrome Uncertain:1
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. -
Familial cancer of breast Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at