Submissions for variant NM_032043.3(BRIP1):c.2071A>C (p.Ile691Leu)

gnomAD frequency: 0.00001  dbSNP: rs587782356

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131304	SCV000186276	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	The p.I691L variant (also known as c.2071A>C), located in coding exon 13 of the BRIP1 gene, results from an A to C substitution at nucleotide position 2071. The isoleucine at codon 691 is replaced by leucine, an amino acid with highly similar properties. This alteration has been identified individuals with breast and ovarian cancer as well as unaffected controls (Tung N et al. J. Clin. Oncol. 2016 May;34(13):1460-8; Easton DF et al. J. Med. Genet., 2016 05;53:298-309; Moyer CL et al. Cancer Res. 2020 Feb;80:857-867; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107(11)). Based on results from an inter-strand cross link damage survival assay, this alteration was characterized as hypomorphic by one group (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000212317	SCV000210848	uncertain significance	not provided	2024-04-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the ability to partially repair interstrand crosslinks possibly resulting in a hypomorphic allele (PMID: 31822495); Observed in individuals with breast and/or ovarian cancer but also in healthy controls (PMID: 26921362, 31822495, 26315354, 26976419); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26976419, 26315354, 26921362, 31822495, 11301010)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229910	SCV000291001	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 691 of the BRIP1 protein (p.Ile691Leu). This variant is present in population databases (rs587782356, gnomAD 0.004%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26921362, 26976419, 31822495). ClinVar contains an entry for this variant (Variation ID: 142280). 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%. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 31822495). 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.
Counsyl	RCV000409629	SCV000490093	uncertain significance	Fanconi anemia complementation group J	2016-11-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000410807	SCV000490094	uncertain significance	Ovarian neoplasm	2016-11-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131304	SCV000689311	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 691 in the helicase domain 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). A functional study has reported that this variant does not impact BRIP1 function in a sensitivity assay to mitomycin C and it does decrease protein stability (PMID: 31822495). This variant has been observed in over 10 individuals affected with breast and/or ovarian cancer (PMID: 26921362, 26976419, 31822495) and in one unaffected individuals from an ovarian cancer case-control study (PMID: 26315354). This variant has also been identified in 6/251368 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.
Genetic Services Laboratory, University of Chicago	RCV001818324	SCV002067710	uncertain significance	not specified	2018-12-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131304	SCV002531389	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315906	SCV004019411	uncertain significance	Familial cancer of breast	2023-03-01	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003315906	SCV004214634	uncertain significance	Familial cancer of breast	2024-03-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212317	SCV004220696	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26921362 (2016), 26976419 (2016), 31822495 (2020)), ovarian cancer (PMID: 31822495 (2020)) as well as in unaffected individuals (PMID: 26315354 (2015)). Published functional studies show that this variant leads to reduced protein stability and partial loss of protein function (PMID: 31822495 (2020)). The frequency of this variant in the general population, 0.000035 (4/113678 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Mayo Clinic Laboratories, Mayo Clinic	RCV000212317	SCV004224420	uncertain significance	not provided	2023-02-08	criteria provided, single submitter	clinical testing	PS3_supporting
GenomeConnect - Invitae Patient Insights Network	RCV000212317	SCV004228482	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-14-2015 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.