Submissions for variant NM_032043.3(BRIP1):c.712A>C (p.Thr238Pro)

gnomAD frequency: 0.00001  dbSNP: rs1490001091

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000532810	SCV000633708	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 238 of the BRIP1 protein (p.Thr238Pro). This variant is present in population databases (no rsID available, 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: 461179). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein 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.
Color Diagnostics, LLC DBA Color Health	RCV000777190	SCV000912881	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 238 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 not been reported in individuals affected with BRIP1-related disorders in the literature. This variant has been identified in 1/251180 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.
Ambry Genetics	RCV000777190	SCV001188379	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	The p.T238P variant (also known as c.712A>C), located in coding exon 6 of the BRIP1 gene, results from an A to C substitution at nucleotide position 712. The threonine at codon 238 is replaced by proline, an amino acid with highly similar properties. This amino acid position is poorly 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315436	SCV004015189	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with proline at codon 238 of the BRIP1 protein (p.Thr238Pro). This variant is not present in population databases gnomad. In-silico predictions show benign computational verdict based on 9 benign predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, LIST-S2, MVP, MutationAssessor, MutationTaster and PrimateAI vs 3 pathogenic predictions from FATHMM-MKL, M-CAP and SIFT and the position is not strongly conserved. This variant has not been published in individuals with BRIP1-related conditions. There are no published functional analyses for this variant. Therefore, it has been classified as a Variant of Uncertain Significance.