Submissions for variant NM_032043.3(BRIP1):c.3507C>A (p.Asp1169Glu)

gnomAD frequency: 0.00001  dbSNP: rs375741316

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205088	SCV000260641	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1169 of the BRIP1 protein (p.Asp1169Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 220245). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV000216628	SCV000278299	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	The p.D1169E variant (also known as c.3507C>A), located in coding exon 19 of the BRIP1 gene, results from a C to A substitution at nucleotide position 3507. The aspartic acid at codon 1169 is replaced by glutamic acid, an amino acid with highly similar properties. This variant was detected in 2/123213 breast cancer cases and 0/5242 controls from the UK (Easton DF et al. J. Med. Genet. 2016 May;53:298-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000255184	SCV000321487	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Easton et al., 2016); This variant is associated with the following publications: (PMID: 26921362)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000255184	SCV002010904	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing