Submissions for variant NM_032043.3(BRIP1):c.2990C>T (p.Thr997Ile)

dbSNP: rs749978235

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000636087	SCV000757519	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-06-09	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 530305). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is present in population databases (rs749978235, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 997 of the BRIP1 protein (p.Thr997Ile).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758995	SCV000887995	uncertain significance	not provided	2018-07-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000636087	SCV000896649	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000772635	SCV000905838	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780050	SCV000917070	uncertain significance	not specified	2017-10-06	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.2990C>T (p.Thr997Ile) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 1/245770 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertian Significance (VUS)," until additional information becomes available.
Sema4, Sema4	RCV000772635	SCV002533666	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-02	criteria provided, single submitter	curation
Ambry Genetics	RCV000772635	SCV002746912	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The p.T997I variant (also known as c.2990C>T), located in coding exon 19 of the BRIP1 gene, results from a C to T substitution at nucleotide position 2990. The threonine at codon 997 is replaced by isoleucine, an amino acid with similar properties. This variant was identified in a cohort of 690 patients with myeloid malignancy (Li ST et al. Leukemia, 2020 06;34:1675-1678). 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	RCV000758995	SCV004031823	uncertain significance	not provided	2023-08-30	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; Reported as a germline variant in individual(s) with myeloid malignancy (Li et al., 2020); This variant is associated with the following publications: (PMID: 31911633, 11301010)
Baylor Genetics	RCV003459518	SCV004217030	uncertain significance	Familial cancer of breast	2023-08-04	criteria provided, single submitter	clinical testing