Submissions for variant NM_032043.3(BRIP1):c.1255C>T (p.Arg419Trp)

gnomAD frequency: 0.00026  dbSNP: rs150624408

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587794	SCV000150029	uncertain significance	not provided	2023-09-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian, breast, prostate, melanoma, pancreatic, or colorectal cancer (Ray et al., 2009; Ramus et al., 2015; Easton et al., 2016; Yurgelun et al., 2017; Weber-Lassalle et al., 2018; Krivokuca et al., 2019; Potjer et al., 2019; Hu et al, 2020); This variant is associated with the following publications: (PMID: 27150160, 29368626, 19935797, 12872252, 24728327, 26315354, 28135145, 26921362, 23555315, 28767289, 30414346, 31159747, 30651582, 32659497, 32283892, 33471991, 35467778, 34284872, 32658311, 29641532)
Ambry Genetics	RCV000116120	SCV000183926	likely benign	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000206467	SCV000261278	likely benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000409993	SCV000489933	uncertain significance	Fanconi anemia complementation group J	2016-08-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000411100	SCV000489934	uncertain significance	Neoplasm of ovary	2016-08-12	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415326	SCV000492806	uncertain significance	Breast carcinoma	2014-12-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116120	SCV000537535	likely benign	Hereditary cancer-predisposing syndrome	2020-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120413	SCV000699660	likely benign	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1255C>T (p.Arg419Trp) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type (IPR006554) 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 0.00037 in 277550 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant was also found in 5/7325 European American women over the age of 70 with no history of cancer (carrier freq=0.0006826, FLOSSIES database). c.1255C>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer, Pancreatic Cancer, Melanoma, Prostate Cancer, and Colorectal Cancer and in unaffected controls (e.g. Ray_2009, Haiman_2013, Ramus_2015, Easton_2016, Yurgelun_2017, Shindo_2017, Potjer_2018, Lassalle_2018, Schubert_2019, Krivokuca_2019, Wang_2019, Dorling_2021, Brady_2022, Krivokuca_2022). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported at our laboratory (CHEK2 c.1100delC [p.Thr367fs], ClinVar: 128042) and in the literature (BRCA1 c.5266dup, [p.Gln1756fs], ClinVar: 17677; Krivokuca_2022), providing supporting evidence for a benign role. Twenty submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: 17 classify the variant as uncertain significance and 3 as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA	RCV000116120	SCV000821953	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000409993	SCV000839384	uncertain significance	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587794	SCV000887977	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with melanoma (PMID: 30414346 (2019)), prostate (PMIDs: 35467778 (2022), 19935797 (2009)), breast and/or ovarian (PMIDs: 34284872 (2022), 33471991 (2021), 26315354 (2019)), or colorectal cancer (PMID: 32283892 (2020)), as well as in healthy controls (PMIDs: 32658311 (2021), 33471991 (2021), 26315354 (2019), see also LOVD (http://databases.lovd.nl/shared/genes/BRIP1). The frequency of this variant in the general population, 0.00059 (18/30608 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000206467	SCV000895112	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000409993	SCV001283867	uncertain significance	Fanconi anemia complementation group J	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262875	SCV001440909	uncertain significance	Familial cancer of breast	2023-07-03	criteria provided, single submitter	clinical testing	Criteria applied: PP3
Institute of Human Genetics, University of Leipzig Medical Center	RCV000409993	SCV001934351	uncertain significance	Fanconi anemia complementation group J	2020-12-03	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587794	SCV002010923	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116120	SCV002531339	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001262875	SCV002584929	uncertain significance	Familial cancer of breast	2022-06-20	criteria provided, single submitter	clinical testing	The BRIP1 c.1255C>T (p.Arg419Trp) missense change has a maximum subpopulation frequency of 0.059% 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, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with ovarian and breast cancer, melanoma, colorectal cancer, hereditary prostate cancer and sporadic pancreatic ductal adenocarcinoma (PMID: 19935797, 26315354, 28135145, 28767289, 29368626, 30414346, 31206626, 32283892, 32659497). To our knowledge, this variant has not been reported in the literature in individuals with Fanconi anemia. In addition, this variant was observed in unaffected controls (PMID: 29368626), and in five individuals reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120413	SCV002760984	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116120	SCV002819174	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149812	SCV003837712	uncertain significance	Breast and/or ovarian cancer	2023-05-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001262875	SCV004019459	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.
PreventionGenetics, part of Exact Sciences	RCV003925121	SCV004741653	uncertain significance	BRIP1-related condition	2024-01-03	criteria provided, single submitter	clinical testing	The BRIP1 c.1255C>T variant is predicted to result in the amino acid substitution p.Arg419Trp. This variant has been observed in individuals with breast, prostate, ovarian, colorectal and pancreatic cancer, as well as in healthy control individuals (Rutter et al. 2003. PubMed ID: 12872252; Ray et al. 2009. PubMed ID: 19935797; Table S1, Bodian et al. 2014. PubMed ID: 24728327 Ramus et al. 2015. PubMed ID: 26315354; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128153/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ITMI	RCV000120413	SCV000084565	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000116120	SCV000787963	uncertain significance	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356264	SCV001551381	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Arg419Trp variant was identified in 6 of 6936 proband chromosomes (frequency: 0.001) from individuals or families with prostate or ovarian cancer and was present in 2 of 8336 control chromosomes (frequency: 0.0002) from healthy individuals (Bodian 2014, Ramus 2015, Ray 2009). The variant was also identified in dbSNP (ID: rs150624408) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, Color Genomics, GeneDx, and 4 clinical laboratories), Clinvitae, MutDB, and the Zhejiang University Database. The variant was not identified in the Cosmic database. The variant was identified in control databases in 95 of 276856 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: include African in 3 of 24020 chromosomes (freq: 0.0001), “Other” in 6 of 6460 chromosomes (freq: 0.001), Latino in 5 of 34350 chromosomes (freq: 0.0001), European in 56 of 126446 chromosomes (freq: 0.0004), Ashkenazi Jewish in 4 of 10148 chromosomes (freq: 0.0004), East Asian in 2 of 18866 chromosomes (freq: 0.0001), Finnish in 1 of 25786 chromosomes (freq: 0.00004), and South Asian in 18 of 30780 chromosomes (freq: 0.001). The p.Arg419 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.