Submissions for variant NM_032043.3(BRIP1):c.2233G>A (p.Ala745Thr)

gnomAD frequency: 0.00006  dbSNP: rs587780235

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586157	SCV000150046	uncertain significance	not provided	2024-03-11	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast, ovarian, and other cancers, but also in unaffected controls (PMID: 31822495, 29368626, 26921362, 26315354, 22692731, 30982232, 33471991, 35171259, 38136308); Published functional studies demonstrate protein stability, lack of mitomycin C and cisplatin sensitivity similar to wild-type, and conflicting impact on protein expression (PMID: 31822495, 38177925); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22895193, 26709662, 22692731, 25846551, 26315354, 25957691, 26832770, 27153395, 26921362, 28420421, 28873162, 29368626, 31159747, 31822495, 33471991, 30982232, 36907870, 35171259, 38177925, 38136308)
Ambry Genetics	RCV000116137	SCV000186759	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	The p.A745T variant (also known as c.2233G>A), located in coding exon 14 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2233. The alanine at codon 745 is replaced by threonine, an amino acid with similar properties. This variant has been reported in multiple studies of individuals considered high-risk for breast and /or ovarian cancer (Catucci I et al. Fam. Cancer. 2012 Sep;11:483-91; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration has also been identified in individuals diagnosed with breast and/or ovarian cancer (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:; Wang J et al. Cancer Med, 2019 05;8:2074-2084; Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). This amino acid position is highly 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.
Genetic Services Laboratory, University of Chicago	RCV000194594	SCV000246813	uncertain significance	not specified	2015-04-11	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000116137	SCV000267030	uncertain significance	Hereditary cancer-predisposing syndrome	2015-10-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116137	SCV000537547	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 745 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study reported this variant to be wild-type in protein stability and sensitivity and cell cycle progression assays to mitomycin C and cisplatin treatment (PMID: 31822495). This variant has been reported in individuals affected with personal or family history of breast and/or ovarian cancer (PMID: 22692731, 26315354, 26921362, 31822495), as well as in unaffected control individuals (PMID: 29368626, 31822495). This variant has also been identified in 20/246024 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477497	SCV000547231	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 745 of the BRIP1 protein (p.Ala745Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 22692731, 26315354, 31822495). ClinVar contains an entry for this variant (Variation ID: 128169). 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 does not substantially affect 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000194594	SCV000699685	uncertain significance	not specified	2019-04-22	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2233G>A (p.Ala745Thr) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 261914 control chromosomes. The observed variant frequency is approximately 1.28 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is benign. c.2233G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Ramus_2015, Maxwell_2016, Easton_2016, Catucci_2012, Weber-Lassalle_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.5946delT, p.Ser1982fsX22), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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 a VUS possibly benign variant.
Counsyl	RCV000662754	SCV000785542	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2017-09-06	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000116137	SCV000821957	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586157	SCV001469477	likely benign	not provided	2023-07-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000586157	SCV002010916	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116137	SCV002531398	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001762241	SCV003928155	uncertain significance	Familial cancer of breast	2023-05-03	criteria provided, single submitter	clinical testing	The BRIP1 c.2233G>A (p.Ala745Thr) missense change has a maximum founder subpopulation frequency of 0.096% and a maximum non-founder subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, but published functional studies demonstrate no damaging effect (PMID: 31822495). The variant has been reported in individuals with breast and/or ovarian cancer (PMID: 22692731, 26315354, 26921362, 27153395, 31822495). This variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV001762241	SCV004019466	uncertain significance	Familial cancer of breast	2023-03-02	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	RCV001762241	SCV004214726	uncertain significance	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000194594	SCV005089857	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116137	SCV005205741	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732686	SCV005350598	uncertain significance	BRIP1-related disorder	2024-04-08	no assertion criteria provided	clinical testing	The BRIP1 c.2233G>A variant is predicted to result in the amino acid substitution p.Ala745Thr. This variant has been reported in individuals with hereditary breast cancer and/or ovarian cancer/pancreatic cancer (Catucci et al. 2012. PubMed ID: 22692731; Ramus et al. 2015. PubMed ID: 26315354, Table S4; Easton et al. 2016. PubMed ID: 26921362, Table S1; Maxwell et al. 2016. PubMed ID: 27153395, Tables S4 and S5; Weber-Lassalle et al. 2018. PubMed ID: 29368626, Table S3; Moyer et al. 2019. PubMed ID: 31822495; Yin et al. 2022. PubMed ID: 35171259, Table e4). It has also been reported in an individual undergoing hereditary cancer testing and interpreted as uncertain significance (Tsaousis et al. 2019. PubMed ID: 31159747, Table S5). However, this variant has also been reported in control individuals (Weber-Lassalle et al. 2018. PubMed ID: 29368626, Table S3). In vitro functional studies suggest that this variant does not impact BRIP1 protein function (Moyer et al. 2019. PubMed ID: 31822495). This variant is reported in 0.096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128169/). This variant could be benign. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.