Submissions for variant NM_032043.3(BRIP1):c.3290A>C (p.Glu1097Ala)

gnomAD frequency: 0.00001  dbSNP: rs876658746

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220039	SCV000274407	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.E1097A variant (also known as c.3290A>C), located in coding exon 19 of the BRIP1 gene, results from an A to C substitution at nucleotide position 3290. The glutamic acid at codon 1097 is replaced by alanine, an amino acid with dissimilar properties. This alteration was observed within 1/64523 individuals with a personal history of breast cancer and in 1/51973 controls (Easton DF et al. J Med Genet, 2016 05;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.
Color Diagnostics, LLC DBA Color Health	RCV000220039	SCV000684255	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-12	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 1097 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250890 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590421	SCV000699719	uncertain significance	not provided	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.3290A>C (p.Glu1097Ala) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 1/131630 control chromosomes at a frequency of 0.0000076, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). To our knowledge, the variant has been reported once in the literature, without strong evidence for causality. In addition, one clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701514	SCV000830317	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1097 of the BRIP1 protein (p.Glu1097Ala). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 230751). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV000590421	SCV002005700	uncertain significance	not provided	2024-09-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in cases and controls in a breast cancer study (PMID: 26921362); This variant is associated with the following publications: (PMID: 26921362, 36243179)
Baylor Genetics	RCV004567530	SCV005059926	uncertain significance	Familial cancer of breast	2023-12-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590421	SCV005623293	uncertain significance	not provided	2024-08-30	criteria provided, single submitter	clinical testing	The BRIP1 c.3290A>C (p.Glu1097Ala) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 26921362 (2016), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)) as well as reportedly healthy individuals (PMID: 26921362 (2016), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared), 36243179 (2022)). The frequency of this variant in the general population, 0.000004 (1/250890 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.