ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1000G>T (p.Ala334Ser) (rs535414791)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160333 SCV000210836 uncertain significance not provided 2015-10-22 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1000G>T at the cDNA level, p.Ala334Ser (A334S) at the protein level, and results in the change of an Alanine to a Serine (GCC>TCC). This variant was identified in an individual undergoing multigene cancer panel testing due to a history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). BRIP1 Ala334Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Ala334Ser occurs at a position that is conserved across species and is located in the Helicase ATP-binding domain (UniProt, Cantor 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRIP1 Ala334Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473511 SCV000547242 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 334 of the BRIP1 protein (p.Ala334Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an an individual affected with breast cancer (PMID: 26921362), and an individual undergoing testing for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 182343). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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 RCV000561620 SCV000666188 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
Color RCV000561620 SCV000689239 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-20 criteria provided, single submitter clinical testing
Mendelics RCV000709554 SCV000839388 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing

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