rs1555572620
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_032043.3(BRIP1):c.3411_3412delTGinsCT(p.Asp1138Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Y1137Y) has been classified as Benign.
Frequency
Consequence
NM_032043.3 missense
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
GnomAD4 genome
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The c.3411_3412delTGinsCT variant (also known as p.D1138Y), located in coding exon 19 of the BRIP1 gene, results from an in-frame deletion of TG and insertion of CT at nucleotide positions 3411 to 3412. This results in the substitution of the aspartic acid residue for a tyrosine residue at codon 1138, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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not specified Uncertain:1
Variant summary: BRIP1 c.3411_3412delinsCT (p.Asp1138Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of at least 5.3e-05 in 150918 control chromosomes (gnomAD v3.1.2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. p.Asp1138Tyr has been reported in the literature in individuals being tested for or affected with cancer, including Lynch syndrome and Hereditary Breast And Ovarian Cancer Syndrome (e.g. Mauer_2013, Lu_2015, Yurgelun_2015). These reports 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. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Breast and/or ovarian cancer Uncertain:1
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Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1138 of the BRIP1 protein (p.Asp1138Tyr). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with breast cancer (PMID: 24113346, 35534704). ClinVar contains an entry for this variant (Variation ID: 570962). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at