ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.397A>T (p.Thr133Ser)

gnomAD frequency: 0.00002  dbSNP: rs764256720
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000525072 SCV000633696 uncertain significance Familial cancer of breast; Fanconi anemia complementation group J 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 133 of the BRIP1 protein (p.Thr133Ser). This variant is present in population databases (rs764256720, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 461169). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. 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 RCV000570140 SCV000666175 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-01 criteria provided, single submitter clinical testing The p.T133S variant (also known as c.397A>T), located in coding exon 4 of the BRIP1 gene, results from an A to T substitution at nucleotide position 397. The threonine at codon 133 is replaced by serine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 120000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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