ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1054T>C (p.Tyr352His) (rs730881632)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160334 SCV000210837 uncertain significance not provided 2014-04-15 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1054T>C at the cDNA level, p.Tyr352His (Y352H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Tyr352His 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 Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Tyr352His occurs at a position that is highly conserved across species and is located in the Helicase ATP-binding domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRIP1 Tyr352His is pathogenic or benign. We consider it to be a variant of uncertain significance. Furthermore, BRIP1 has been only recently described in association with cancer predisposition and the risks are not well understood.
Ambry Genetics RCV000213947 SCV000276575 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000542718 SCV000633531 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 352 of the BRIP1 protein (p.Tyr352His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs730881632, ExAC 0.001%). This variant has been reported in an individual affected with breast cancer and an unaffected individual (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 182344). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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