Submissions for variant NM_032043.2(BRIP1):c.2863A>C (p.Asn955His) (rs587782244)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130948	SCV000185862	uncertain significance	Hereditary cancer-predisposing syndrome	2017-05-01	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color	RCV000130948	SCV000903150	uncertain significance	Hereditary cancer-predisposing syndrome	2018-05-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000367894	SCV000329163	uncertain significance	not provided	2018-10-02	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.2863A>C at the cDNA level, p.Asn955His (N955H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant has been observed in three individuals with a personal history of breast cancer (Wong 2011, Tung 2015, Easton 2016). BRIP1 Asn955His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCA1 Binding Domain (Cantor 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Asn955His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000464105	SCV000547355	uncertain significance	Familial cancer of breast; Fanconi anemia, complementation group J	2018-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with histidine at codon 955 of the BRIP1 protein (p.Asn955His). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (rs587782244, ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 21409391). ClinVar contains an entry for this variant (Variation ID: 142113). 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 tolerated, 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.