rs150624408
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6
The NM_032043.3(BRIP1):c.1255C>T(p.Arg419Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,613,364 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R419G) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00030 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00026 ( 1 hom. )
Consequence
BRIP1
NM_032043.3 missense
NM_032043.3 missense
Scores
4
13
2
Clinical Significance
Conservation
PhyloP100: 2.97
Genes affected
BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.75
BP6
Variant 17-61799185-G-A is Benign according to our data. Variant chr17-61799185-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128153.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=5, Uncertain_significance=18}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRIP1 | NM_032043.3 | c.1255C>T | p.Arg419Trp | missense_variant | 9/20 | ENST00000259008.7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRIP1 | ENST00000259008.7 | c.1255C>T | p.Arg419Trp | missense_variant | 9/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes 0.000296 AC: 45AN: 151954Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000358 AC: 90AN: 251150Hom.: 1 AF XY: 0.000413 AC XY: 56AN XY: 135718
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GnomAD4 exome AF: 0.000265 AC: 387AN: 1461410Hom.: 1 Cov.: 32 AF XY: 0.000301 AC XY: 219AN XY: 727034
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GnomAD4 genome 0.000296 AC: 45AN: 151954Hom.: 1 Cov.: 32 AF XY: 0.000310 AC XY: 23AN XY: 74232
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:21Benign:5Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:4Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 17, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | True Health Diagnostics | Feb 20, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 05, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Aug 18, 2022 | - - |
Fanconi anemia complementation group J Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 03, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 12, 2016 | - - |
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 01, 2023 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2024 | 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, colorectal, and other cancers (PMID: 19935797, 26315354, 26921362, 28135145, 29368626, 30651582, 30414346, 32659497, 34326862, 35534704, 33850299); 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, 34326862, 35534704, 33850299) - |
Familial cancer of breast Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jun 20, 2022 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 02, 2023 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 03, 2023 | Criteria applied: PP3 - |
not specified Uncertain:1Benign:1Other:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 04, 2023 | 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. - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 23, 2023 | - - |
BRIP1-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2024 | 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. - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Ovarian neoplasm Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 12, 2016 | - - |
Breast carcinoma Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 05, 2014 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
| Likely benign, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Feb 15, 2024 | According to the ACMG SVI adaptation criteria we chose these criteria: BS1 (supporting benign): 84x het in gnomAD non Cancer, in V4 432X, BS2 (strong benign): 1x homzygous in gnomAD nonCancer, in v4 2X - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at