Submissions for variant NM_032043.3(BRIP1):c.2543G>A (p.Arg848His)

gnomAD frequency: 0.00003  dbSNP: rs374334794

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130056	SCV000184883	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-03	criteria provided, single submitter	clinical testing	The p.R848H variant (also known as c.2543G>A), located in coding exon 17 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2543. The arginine at codon 848 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in a woman with bilateral breast cancer and ovarian cancer who had a family history of breast cancer and leukemia (Kim H et al. Cancer Res Treat 2016 Jan). This alteration was also seen in a Swedish melanoma family and segregated with disease in three individuals (Tuominen R et al. Genes Chromosomes Cancer. 2016 Jul;55(7):601-11). This variant has also been reported in the homozygous state in multiple individuals diagnosed with Fanconi anemia (Steinberg-Shemer O et al. Haematologica, 2020 07;105:1825-1834, Kamal L et al. Cold Spring Harb Mol Case Stud, 2020 10;6:). In vitro functional studies showed that this variant has deficient helicase activity, however, the physiological relevance of this finding is unclear (Kamal L et al. Cold Spring Harb Mol Case Stud, 2020 10;6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Counsyl	RCV000663220	SCV000786407	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2018-04-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699539	SCV000828254	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 848 of the BRIP1 protein (p.Arg848His). This variant is present in population databases (rs374334794, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, Fanconi anemia, melanoma, and/or ovarian cancer (PMID: 26790966, 27074266, 29368626, 31558676, 33028645). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 141499). 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 expected to disrupt BRIP1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 33028645). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000699539	SCV000896650	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	RCV000130056	SCV000909762	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 848 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A function study has reported that this variant lacks helicase activity in vitro (PMID: 33028645). This variant has been observed in at least seven individuals affected with breast and/or ovarian cancer (PMID: 26790966, 27074266, 29368626, 33471991; Leiden Open Variation Database DB-ID BRIP1_000121; Color internal data). In one of the individual affected with ovarian cancer, the proband and other carrier family members were also affected with cutaneous malignant melanoma, squamous cell carcinoma of the skin and liver cancer (PMID: 27074266). This variant also has been reported in at least two homozygous carriers diagnosed with Fanconi anemia (PMID: 31558676, 33028645). In one Fanconi anemia case, the carrier lymphocytes were confirmed to exhibit chromosomal breakage after mitomycin C treatment (PMID: 33028645). This variant also has been reported in unaffected individuals in cancer case-control studies (PMID: 31214711, 32980694, 33471991; Leiden Open Variation Database DB-ID BRIP1_000121). This variant has been identified in 1/31386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneDx	RCV001194712	SCV001777038	uncertain significance	not provided	2019-08-19	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with breast cancer or ovarian cancer and in a family with multiple cases of melanoma (Kim 2016, Tuominen 2016, Weber-Lassalle 2018); This variant is associated with the following publications: (PMID: 31558676, 29368626, 27074266, 26709662, 26790966)
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273958	SCV002558935	likely pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460909	SCV004217033	uncertain significance	Familial cancer of breast	2023-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255230	SCV005205363	pathogenic	Fanconi anemia complementation group J	2024-06-04	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2543G>A (p.Arg848His) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251348 control chromosomes. c.2543G>A has been reported in the literature in homozygous state in individuals affected with Fanconi Anemia Complementation Group J (Kamal_2020, Steinberg-Shemer_2020). It has also been reported in heterozygous state in individuals affected with cutaneous malignant melanoms (Tuominen_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in increased chromosomal breakage after exposure to increasing concentrations of mitomycin C in peripheral blood lymphocytes of an affected individual and loss of helicase activity of the mutant protein in an in vitro assay (Kamal_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33028645, 315588676, 27074266). ClinVar contains an entry for this variant (Variation ID: 141499). Based on the evidence outlined above, the variant was classified as pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004760390	SCV005373762	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-09-09	criteria provided, single submitter	curation	According to the ACMG SVI adaptation criteria we chose these criteria: PS3 (strong pathogenic): Kamal et al. (2020) PMID:33028645, PM2 (supporting pathogenic): gnomAD 4.1.0: 0,0006% gnomAD 3.1 (non-cancer): 0, PM3 (medium pathogenic): homozygous in 2 individuals with FA by Kamal (2020), PMID: 33028645 (in one FA case, the carrier lymphocytes were confirmed to exhibit chromosomal breakage after mitomycin C treatment) + homozygous in 1 individual with FA by Steinberg-Shemer (2020), PMID: 31558676, PP3 (supporting pathogenic): REVEL: 0.93
Leiden Open Variation Database	RCV001194712	SCV001364478	uncertain significance	not provided	2019-08-13	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
King Laboratory, University of Washington	RCV001255230	SCV001429629	pathogenic	Fanconi anemia complementation group J	2020-08-13	no assertion criteria provided	clinical testing