Submissions for variant NM_032043.2(BRIP1):c.1952T>C (p.Ile651Thr) (rs757305097)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222634	SCV000273217	uncertain significance	Hereditary cancer-predisposing syndrome	2017-09-11	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color	RCV000222634	SCV000689298	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000218247	SCV000278899	uncertain significance	not provided	2018-06-21	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.1952T>C at the cDNA level, p.Ile651Thr (I651T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant was reported in an unaffected control individual but absent from breast and ovarian cancer cases (Weber-Lassalle 2018). BRIP1 Ile651Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Ile651Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000230038	SCV000290998	uncertain significance	Familial cancer of breast; Fanconi anemia, complementation group J	2018-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 651 of the BRIP1 protein (p.Ile651Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs757305097, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 229862). 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.