Submissions for variant NM_032043.3(BRIP1):c.1594A>G (p.Met532Val)

gnomAD frequency: 0.00001  dbSNP: rs876658383

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214562	SCV000273521	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-27	criteria provided, single submitter	clinical testing	The p.M532V variant (also known as c.1594A>G), located in coding exon 10 of the BRIP1 gene, results from an A to G substitution at nucleotide position 1594. The methionine at codon 532 is replaced by valine, an amino acid with highly 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	RCV000532257	SCV000633562	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 532 of the BRIP1 protein (p.Met532Val). This variant is not present in population databases (gnomAD no frequency). 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: 230095). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 95%. 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	RCV000214562	SCV000684140	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 532 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780069	SCV000917091	uncertain significance	not specified	2018-12-26	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1594A>G (p.Met532Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246136 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1594A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003462421	SCV004214731	uncertain significance	Familial cancer of breast	2023-09-27	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001194750	SCV001364526	uncertain significance	not provided	2019-03-03	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Andreas Laner.