Submissions for variant NM_032043.3(BRIP1):c.133G>A (p.Glu45Lys)

dbSNP: rs587781292

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000222594	SCV000279640	uncertain significance	not provided	2023-04-17	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; This variant is associated with the following publications: (PMID: 26315354, 11301010)
Color Diagnostics, LLC DBA Color Health	RCV000582447	SCV000689257	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 45 of the BRIP1 protein. Computational prediction tool 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 1/31404 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686973	SCV000814518	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-08-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 45 of the BRIP1 protein (p.Glu45Lys). This variant is present in population databases (rs587781292, 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: 234641). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	RCV000582447	SCV001171407	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	The p.E45K variant (also known as c.133G>A), located in coding exon 2 of the BRIP1 gene, results from a G to A substitution at nucleotide position 133. The glutamic acid at codon 45 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586638	SCV005076432	uncertain significance	not specified	2024-04-26	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.133G>A (p.Glu45Lys) results in a conservative amino acid change located in the Helicase-like, DEXD box c2 type domain (IPR006554) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes. 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.133G>A in individuals affected with Fanconi Anemia Complementation Group J and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 234641). Based on the evidence outlined above, the variant was classified as uncertain significance.