Submissions for variant NM_032043.3(BRIP1):c.446A>G (p.Asp149Gly)

dbSNP: rs770613242

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809093	SCV000949233	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 149 of the BRIP1 protein (p.Asp149Gly). This variant is present in population databases (rs770613242, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 653340). 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 glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV001022529	SCV001184281	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	clinical testing	The p.D149G variant (also known as c.446A>G), located in coding exon 4 of the BRIP1 gene, results from an A to G substitution at nucleotide position 446. The aspartic acid at codon 149 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in a cohort of 1010 breast and/or ovarian cancer patients from India who were tested with a multi-gene panel and classified as a variant of unknown significance by the authors (Singh J et al. Breast Cancer Res. Treat., 2018 Feb). 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.
Color Diagnostics, LLC DBA Color Health	RCV001022529	SCV004360294	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-24	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 149 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast or ovarian cancer (PMID: 29470806). This variant has been identified in 1/251326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.