Submissions for variant NM_032043.3(BRIP1):c.751C>T (p.Arg251Cys)

gnomAD frequency: 0.00004  dbSNP: rs752309409

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165345	SCV000216069	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	The p.R251C pathogenic mutation (also known as c.751C>T), located in coding exon 6 of the BRIP1 gene, results from a C to T substitution at nucleotide position 751. The arginine at codon 251 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in one individual diagnosed with Fanconi anemia along with a second alteration in BRIP1 (Chandrasekharappa SC et al. Blood 2013 May;121(22):e138-48). This alteration was also identified the homozygous state in a cohort of Israeli patients diagnosed with Fanconi anemia (Steinberg-Shemer O et al. Haematologica. 2019 Sep), as well as in 55-year-old identical twins, both affected with cancer and a late-onset and less severe form of Fanconi anemia, leading the authors to speculate that this may be a hypomorphic allele (Stevens H et al. Am. J. Hematol. 2016 Dec;91:1273-1276). This alteration has been reported in 0/7636 unselected prostate cancer patients and 1/12,366 male controls of Japanese ancestry (Momozawa Y et al. J. Natl. Cancer Inst. 2019 Jun). Functional studies showed this alteration to be deficient in helicase activity, as well as DNA and ATP binding. In addition, cells expressing this alteration showed increased cell death in response to DNA damaging agents compared to wild type (Guo M et al. J. Biol. Chem. 2014 Apr;289:10551-65). Structural analysis indicates that p.R251C likely disrupts ligand binding in a functionally significant and sensitive region (Ambry internal data, He Y et al. EMBO Rep. 2010 Mar;11:180-6; He Y et al. Nature. 2016 05;533:359-65). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000206065	SCV000260454	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 251 of the BRIP1 protein (p.Arg251Cys). This variant is present in population databases (rs752309409, gnomAD 0.0009%). This missense change has been observed in individuals with breast cancer and/or Fanconi anemia (PMID: 23613520, 26556299, 27427815, 31558676, 31586946). ClinVar contains an entry for this variant (Variation ID: 185848). 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: 24573678, 27107905). 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.
GeneDx	RCV000219928	SCV000279333	likely pathogenic	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Observed in the homozygous and compound heterozygous state in individuals with Fanconi anemia referred for genetic testing at GeneDx and in the published literature (Chandrasekharappa et al., 2013; Stevens et al., 2016; Bogliolo et al., 2020); Observed in individuals with breast cancer (Easton et al., 2016; Schrader et al., 2016); Published functional studies demonstrate a damaging effect: deficient in vitro complementation in a BRIP1 null cell line and reduced DNA binding (Guo et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25374583, 31586946, 33028645, 23613520, 28235761, 27107905, 26596371, 26921362, 26556299, 27427815, 33137625, 31558676, 31214711, 24573678, 19763819, 22692731, 11301010, 33471991)
Color Diagnostics, LLC DBA Color Health	RCV000165345	SCV000903617	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 251 in the helicase domain 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). Functional studies have shown that the mutant protein shows no DNA helicase activity, reduced ATP binding activity, reduced DNA-dependent ATPase activity, and failed to complement BRIP1-null cell line (PMID: 24573678, 27107905). This variant has been reported in two homozygous individuals affected with Fanconi anemia (PMID: 27427815, 31558676), as well as in an individual affected with Fanconi anemia in compound heterozygous state with a deleterious p.His396Asp variant (PMID: 23613520) (ClinVar variation ID: 659729). In a large breast cancer case-control study, this variant has been observed in 3/60463 cases and 2/53459 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID BRIP1_000010). This variant has also been reported in 2 unaffected control individuals in pancreatic and prostate cancer case-control studies and absent in affected individuals (PMID: 31214711, 32980694). This variant has been identified in 3/251170 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been shown to impair BRIP1 protein function. The observation of this variant in biallelic individuals affected with autosomal recessive Fanconi anemia indicates that this variant contributes to disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV001781512	SCV002022088	likely pathogenic	Fanconi anemia complementation group J	2019-04-19	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225482	SCV002505045	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001781512	SCV002511901	pathogenic	Fanconi anemia complementation group J	2022-04-29	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.751C>T (p.Arg251Cys) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251170 control chromosomes. c.751C>T has been reported in the literature in multiple individuals affected with Fanconi Anemia Complementation Group J in the homozygous and compound heterozygous state (Chandrasekharappa_2013, Stevens_2016, Steinberg-Shermer_2020, Bogliolo_2020) as well as in patients with breast cancer in the heterozygous state (e.g. Schrader_2016). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was shown to abolish DNA helicase activity and DNAprotein displacement activity (Guo_2014). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five submitters classified the variant as likely pathogenic/pathogenic while one classified the variant as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000165345	SCV002533741	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-10-18	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000165345	SCV004014915	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003316042	SCV004019366	likely pathogenic	Familial cancer of breast	2023-02-28	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24573678]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23613520, 31586946].
Baylor Genetics	RCV003316042	SCV004214690	pathogenic	Familial cancer of breast	2023-10-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000219928	SCV004220734	likely pathogenic	not provided	2022-09-16	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000012 (3/251170 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26921362 (2016), 26556299 (2016)), Fanconi anemia (PMID: 31586946 (2020), 31558676 (2020), 27427815 (2016), 23613520 (2013)), and pancreatic cancer (PMID: 31214711 (2020)). In a large breast cancer association study, this variant was reported in individuals affected with breast cancer and in healthy controls (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRIP1). Functional studies reported this variant to be damaging to cell survival, DNA helicase activity, DNA binding, ATP hydrolysis activity and binding, as well as DNA repair functions (PMID: 27107905 (2016), 24573678 (2014)). 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, this variant is classified as likely pathogenic.
Counsyl	RCV000662796	SCV000785613	uncertain significance	Fanconi anemia complementation group J; Neoplasm of ovary	2017-10-10	flagged submission	clinical testing