Submissions for variant NM_032043.2(BRIP1):c.3236T>C (p.Ile1079Thr) (rs150813402)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116154	SCV000150063	uncertain significance	not provided	2017-04-03	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.3236T>C at the cDNA level, p.Ile1079Thr (I1079T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Ile1079Thr was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Ile1079Thr occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 Ile1079Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000204707	SCV000261454	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 1079 of the BRIP1 protein (p.Ile1079Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs150813402, ExAC 0.01%) but has not been reported in the literature in individuals with a BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 128185). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000218787	SCV000273236	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-29	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
Counsyl	RCV000663136	SCV000786280	uncertain significance	Fanconi anemia, complementation group J; Neoplasm of ovary	2018-04-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000116154	SCV000888000	uncertain significance	not provided	2018-07-09	criteria provided, single submitter	clinical testing
Color	RCV000218787	SCV000906472	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-25	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000780057	SCV000917078	uncertain significance	not specified	2018-04-30	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.3236T>C (p.Ile1079Thr) results in a non-conservative amino acid change located outside of any known functional domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This frequency is lower than expected for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer (7.8e-06 vs 6.3e-05), allowing no conclusion about variant significance. The c.3236T>C has been reported in the literature in individuals affected with Breast Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.