ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1045G>A (p.Ala349Thr) (rs149364097)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431413 SCV000523741 uncertain significance not provided 2016-02-15 criteria provided, single submitter clinical testing The A349T variant in the BRIP1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A349T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A349T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs within the helicase ATP-binding domain, at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret A349T as a variant of uncertain significance.
Ambry Genetics RCV000563742 SCV000666214 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Insufficient or conflicting evidence
Invitae RCV000706778 SCV000835848 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 349 of the BRIP1 protein (p.Ala349Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 383362). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Ala349Pro) has been determined to be pathogenic (PMID: 16116424, 24448499, 16973432, 20639400, 27107905). This suggests that the alanine residue is critical for BRIP1 protein function and that other missense substitutions at this position may also be pathogenic. 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.

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