Submissions for variant NM_032043.3(BRIP1):c.1268A>G (p.Asp423Gly)

gnomAD frequency: 0.00001  dbSNP: rs746778889

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572388	SCV000666253	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The p.D423G variant (also known as c.1268A>G), located in coding exon 8 of the BRIP1 gene, results from an A to G substitution at nucleotide position 1268. The aspartic acid at codon 423 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636091	SCV000757523	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-12	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 423 of the BRIP1 protein (p.Asp423Gly). This variant is present in population databases (rs746778889, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 481662). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRIP1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.
GeneDx	RCV002526826	SCV003194864	uncertain significance	not provided	2022-07-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003459323	SCV004214767	uncertain significance	Familial cancer of breast	2023-09-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000572388	SCV004362944	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 423 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282612 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.