ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.728T>C (p.Ile243Thr)

gnomAD frequency: 0.00003  dbSNP: rs587781860
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130174 SCV000185011 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-17 criteria provided, single submitter clinical testing The p.I243T variant (also known as c.728T>C), located in coding exon 6 of the BRIP1 gene, results from a T to C substitution at nucleotide position 728. The isoleucine at codon 243 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Tung N et al. J. Clin. Oncol. 2016 May;34(13):1460-8). This alteration was also identified in a cohort of female patients with a family history of breast and/or ovarian cancer of Tatar descent (Brovkina OI et al. Front Oncol. 2018 Oct;8:421). In another study, this alteration was observed in 0/3236 cases with invasive epithelial ovarian cancer and 1/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
Invitae RCV000473070 SCV000547305 uncertain significance Familial cancer of breast; Fanconi anemia complementation group J 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 243 of the BRIP1 protein (p.Ile243Thr). This variant is present in population databases (rs587781860, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and colorectal cancer (PMID: 26315354, 26976419, 28135145, 35264596). ClinVar contains an entry for this variant (Variation ID: 141590). 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 with a negative predictive value of 80%. 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.
GeneDx RCV000484934 SCV000569204 uncertain significance not provided 2023-05-25 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 26315354, 26976419, 28135145, 32885271, 35264596, 30333958)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484934 SCV000889224 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000130174 SCV000911037 likely benign Hereditary cancer-predisposing syndrome 2016-10-06 criteria provided, single submitter clinical testing
Mendelics RCV003492596 SCV001140787 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000709557 SCV001369084 uncertain significance Fanconi anemia complementation group J 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance.
MGZ Medical Genetics Center RCV000990023 SCV002579193 uncertain significance Familial cancer of breast 2022-04-25 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003321513 SCV004026891 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000990023 SCV004214769 uncertain significance Familial cancer of breast 2023-09-05 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000484934 SCV001553945 uncertain significance not provided no assertion criteria provided clinical testing The BRIP1 p.Ile243Thr variant was identified in 2 of 9968 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer (Tung 2016), in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with with suspected Lynch syndrome (Yurgelun 2015), and in 1 of 6862 control chromosomes (frequency: 0.0002) from healthy control individuals in an ovarian cancer study (Ramus 2015). The variant was also identified in dbSNP (ID: rs587781860) as “With Uncertain significance allele” and ClinVar (as uncertain significance by Ambry Genetics, Invitae, GeneDx, Mendelics, and Quest Diagnostics). The variant was identified in control databases in 8 of 245908 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European Non-Finnish population in 8 of 111406 chromosomes (freq: 0.00007), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The variant was identified by our laboratory with a co-occurring, pathogenic BRCA2 variant (c.5946del, p.Ser1982Argfs*22), increasing the likelihood that the BRIP1 p.Ile243Thr variant does not have clinical significance. The p.Ile243 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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