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

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130948	SCV000185862	uncertain significance	Hereditary cancer-predisposing syndrome	2018-05-17	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
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	2019-12-27	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.
Color	RCV000130948	SCV000903150	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000367894	SCV001134019	uncertain significance	not provided	2018-11-05	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV001192822	SCV001361197	uncertain significance	not specified	2019-05-24	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2863A>C (p.Asn955His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250742 control chromosomes (gnomAD). c.2863A>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Wong_2011, Easton_2016, Tung_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.