Submissions for variant NM_032043.3(BRIP1):c.749C>G (p.Thr250Arg)

dbSNP: rs1555609275

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550168	SCV000633712	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-02-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 250 of the BRIP1 protein (p.Thr250Arg). 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: 461181). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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	RCV000568986	SCV000661493	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	clinical testing	The p.T250R variant (also known as c.749C>G), located in coding exon 6 of the BRIP1 gene, results from a C to G substitution at nucleotide position 749. The threonine at codon 250 is replaced by arginine, 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	RCV001193529	SCV001362424	uncertain significance	not specified	2021-09-08	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.749C>G (p.Thr250Arg) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251170 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.749C>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001252983	SCV001428470	uncertain significance	Familial cancer of breast	2019-02-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001252983	SCV005059284	uncertain significance	Familial cancer of breast	2024-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV004777713	SCV005389964	uncertain significance	not provided	2024-04-16	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: 11301010)