Submissions for variant NM_032043.3(BRIP1):c.3412G>A (p.Asp1138Asn)

dbSNP: rs587780249

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223506	SCV000276792	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	clinical testing	The p.D1138N variant (also known as c.3412G>A), located in coding exon 19 of the BRIP1 gene, results from a G to A substitution at nucleotide position 3412. The aspartic acid at codon 1138 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly 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.
Invitae	RCV000459206	SCV000547283	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2016-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 1138 of the BRIP1 protein (p.Asp1138Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (ExAC, <0.01%) but has not been reported in the literature in individuals with a BRIP1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging "; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587926	SCV000699723	uncertain significance	not provided	2016-07-15	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.3412G>A (p.Asp1138Asn) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/120914 control chromosomes, which does not rule out the pathogenicity of this variant. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. In addition, one clinical diagnostic laboratory classified this variant as VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Mendelics	RCV000709525	SCV000839350	uncertain significance	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000587926	SCV002319006	uncertain significance	not provided	2023-07-26	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 a patient with breast cancer (Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 20159562, 21127055, 35264596)