Submissions for variant NM_032043.2(BRIP1):c.3622G>C (p.Asp1208His) (rs760589795)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487009	SCV000565870	uncertain significance	not provided	2015-03-05	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.3622G>C at the cDNA level, p.Asp1208His (D1208H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Asp1208His 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 Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Asp1208His occurs at a position that is conserved across species and is not found in a published functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRIP1 Asp1208His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000689972	SCV000817645	uncertain significance	Familial cancer of breast; Fanconi anemia, complementation group J	2018-06-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with histidine at codon 1208 of the BRIP1 protein (p.Asp1208His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 418650). 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.
True Health Diagnostics	RCV000678993	SCV000805253	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-27	no assertion criteria provided	clinical testing

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