Submissions for variant NM_032043.3(BRIP1):c.3605A>G (p.Glu1202Gly)

gnomAD frequency: 0.00001  dbSNP: rs776010326

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165933	SCV000216689	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	The p.E1202G variant (also known as c.3605A>G), located in coding exon 19 of the BRIP1 gene, results from an A to G substitution at nucleotide position 3605. The glutamic acid at codon 1202 is replaced by glycine, an amino acid with similar properties. 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	RCV000214877	SCV000278906	uncertain significance	not provided	2023-08-08	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; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233466	SCV000291045	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1202 of the BRIP1 protein (p.Glu1202Gly). This variant is present in population databases (rs776010326, gnomAD 0.0009%). 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: 186352). 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.
Color Diagnostics, LLC DBA Color Health	RCV000165933	SCV000684268	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-29	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 1202 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 cancer (PMID: 26689913). This variant has been identified in 1/250658 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003230428	SCV003926635	uncertain significance	Familial cancer of breast	2023-05-29	criteria provided, single submitter	clinical testing	a variant of uncertain significance was detected in the BRIP1 gene (c.3605A>G).This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non‐polar, at codon 1202 of the BRIP1 protein (p.Glu1202Gly). This amino acid position is not well conserved (PhyloP=1.6) . This variant is present in population databases (rs776010326, gnomAD 0.0009%). 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: 186352). In silico analysis supports that this missense variant does not alter protein structure/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.
PreventionGenetics, part of Exact Sciences	RCV004535122	SCV004727644	uncertain significance	BRIP1-related disorder	2024-02-28	no assertion criteria provided	clinical testing	The BRIP1 c.3605A>G variant is predicted to result in the amino acid substitution p.Glu1202Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.