rs55770810
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong
The ENST00000357654.9(BRCA1):c.5095C>T(p.Arg1699Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1699Q) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
BRCA1
ENST00000357654.9 missense
ENST00000357654.9 missense
Scores
15
2
2
Clinical Significance
Conservation
PhyloP100: 3.39
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 16 uncertain in ENST00000357654.9
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43063930-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37636.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.843
PP5
Variant 17-43063931-G-A is Pathogenic according to our data. Variant chr17-43063931-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55396.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063931-G-A is described in Lovd as [Pathogenic]. Variant chr17-43063931-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.5095C>T | p.Arg1699Trp | missense_variant | 17/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.5095C>T | p.Arg1699Trp | missense_variant | 17/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251242Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135804
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:44
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:18
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genologica Medica | Jan 01, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 27, 2018 | The c.5095C>T (p.Arg1699Trp) variant in the BRCA1 gene has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 17574969, 21324516, 21356067 and 22889855). This variant is also reported in trans with p.Ser198Argfs*35 in a patient with Fanconi anemia (PMID 25472942). This variant is observed in gnomAD with low minor allele frequency (6/246072). Functional assays have shown that this change disrupts BRCA1 binding ability and transcriptional activity (PMID 11157798, 17308087 and 23867111 ). The amino acid Arg 1699 is a highly conserved residue, and the p.Arg1699Trp change is predicted to be deleterious by multiple prediction algorithms. Crystal structure analysis showed that this variant significantly reduce peptide binding through loss of contacts to the main chain of the Phe(+3) residue and a destabilization of the folding BRCT domain (PMID: 21473589). Therefore, the c.5095C>T (p.Arg1699Trp) variant in the BRCA1 gene is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Feb 20, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Unidad Asesoramiento Genetico Oncologico Falp, Instituto Oncologico Fundacion Arturo Lopez Perez | Aug 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 21, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jul 28, 2017 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jan 22, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Bioinformatics dept., Datar Cancer Genetics Limited, India | Jun 20, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Oct 20, 2015 | - - |
not provided Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Aug 12, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Apr 03, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2020 | Published functional studies demonstrate a damaging effect: transcription activation, homologous recombination, and protein binding support a deleterious effect (Worley 2002, Coquelle 2011, Nikolopoulos 2007, Bouwman 2013); Observed with a pathogenic variant on the opposite allele (in trans) in a woman with multiple congenital anomalies and a cellular phenotype consistent with a Fanconi anemia-like disorder and breast cancer at age 23 (Sawyer 2015); Observed in several individuals with breast and/or ovarian cancer, including a de novo observation, and has been found to segregate with disease in at least three families (Vallon-Christersson 2001, Rhiem 2007, Spurdle 2012, Kuusisto 2013, Laraqui 2013, Zorrieh Zahra 2016, Antonucci 2017, Meisel 2017, Alhuqail 2018); Multifactorial studies suggest this variant is associated with breast cancer (Lindor 2012, Spurdle 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5214C>T; This variant is associated with the following publications: (PMID: 15235020, 31447099, 31454914, 31472684, 30825404, 30765603, 30322717, 29712865, 29446198, 30078507, 30458859, 30103829, 30702160, 29161300, 28724667, 29907814, 28831036, 28477318, 29478780, 29625052, 29422015, 29339979, 29435075, 29297111, 29975922, 27478808, 27272900, 26681312, 26689913, 25814778, 23289006, 17924331, 25782689, 22889855, 23867111, 21990134, 21473589, 17493881, 25472942, 20516115, 18519686, 17308087, 16528612, 15133503, 15133502, 12496476, 28283652, 28281021, 24448499, 23479189, 23697973, 25948282, 25236687, 29133208, 25859162, 28651617, 27225819, 28176296, 20665887, 15290653, 15125843, 28490613, 18182601, 18835712, 14746861, 22366370, 23374397, 26843898, 23967248, 19563646, 20727672, 21356067, 11157798, 17574969, 21965345, 23231788, 24728189, 21324516, 25637381, 21520273, 21447777, 19200354, 24055113, 17305420, 28324225, 28265380, 26884819, 29348823) - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | BRCA1: PP1:Strong, PS3, PM1, PM5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 13, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 19, 2020 | This variant has been reported as pathogenic and/or having a deleterious effect on BRCA1 protein function in the published literature (PMIDs: 24845084 (2014), 22889855 (2012), 11157798 (2001), 27272900 (2016), 17574969 (2007), 26689913 (2015)), 31454914 (2019), 31472684 (2019) and was found in trans with another BRCA1 variant in a patient with a recently described Fanconi Anemia subtype (PMID 25472942 (2015)). Functional studies found that this variant impaired folding and transcriptional activity (PMIDs: 11157798 (2001), 24845084 (2014), 27272900 (2016)). Based on the available information, the variant is classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1699 of the BRCA1 protein (p.Arg1699Trp). This variant is present in population databases (rs55770810, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer, Fanconi anemia, and/or ovarian cancer (PMID: 11157798, 17574969, 21324516, 21356067, 22889855, 25472942). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55396). 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 BRCA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17308087, 17924331, 20516115, 21473589, 21990134, 23867111). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 01, 2021 | Variant summary: BRCA1 c.5095C>T (p.Arg1699Trp) results in a non-conservative amino acid change located in the BRCT 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 2.4e-05 in 251742 control chromosomes. c.5095C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Vallon-Christersson_2001, Meindl_2002, Mohammadi_2009, Easton_2007, Antonucci_2016, Gao_2018, Momozawa_2018, Alhuqail_2018, Dorling_2021). These data indicate that the variant is very likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function (Vallon-Christersson_2001, Bouwman_2013, Coquelle_2011) . The most pronounced variant effect results in a drastic reduction in phosphopeptide binding affinity as compared to the wild-type (Coquelle_2011). Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Arg1699Trp variant in BRCA1 is an established pathogenic variant that has been identified in multiple individuals of various ethnic backgrounds with BRCA1-associated cancer and segregrated with disease in multiple families (Vallon-Christersson 2001, Rhiem 2007, Kuusisto 2011, Zhang 2011, Spurdle 2012, Larqui 2013, Song 2014, Zahra 2016, Alemar 2017, Barrios 2017, Hirasawa 2017, Alhuqail 2018, Rebbeck 2018, Bhaskaran 2019, Concolino 2019). It was also identfied as a de novo change in 1 individual with early onset breast cancer (paternity confirmed; Antonucci 2017) and in the compound heterozygous state with a loss-of-function BRCA1 variant in an individual with breast cancer, short stature, intellectual disability, and multiple congenital anomalies (Sawyer 2015). Multiple in vitro analyses as well as multifactorial probability models are consistent with pathogenicity (Carvalho 2007, Easton 2007, Lee 2010, Coquelle 2011, Spurdle 2012, Bouwman 2013). This variant is present in 6/251242 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and was classified as pathogenic in ClinVar by several labories and the ClinGen-approved ENIGMA expert panel (Variation ID 55396). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PS2, PS4, PP1_Strong, PM2_Supporting, PS3_Moderate, PP3. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 22, 2024 | Criteria applied: PP4_VSTR,PS3,PM2_SUP - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 15, 2023 | This missense variant replaces arginine with tryptophan at codon 1699 of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant reduces transcriptional activity (PMID: 11157798, 12496476, 17308087, 22889855) and phosphopeptide binding of the BRCA1 protein (PMID: 21473589) and fails to rescue the lethality phenotype in BRCA1-deficient mouse embryonic stem cells (PMID: 23867111). This variant has been reported in many individuals affected with breast and/or ovarian cancer (PMID: 11157798, 17279547, 17574969, 21324516, 22889855, 23289006, 28265380, 30287823) and in the compound heterozygous state in an individual affected with Fanconi anemia (PMID: 25472942). This variant has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000387). In addition, multifactorial likelihood models using health history, in silico, and tumor phenotype data have suggested this variant have a high probability of being pathogenic (PMID: 17279547, 17924331, 21990134). This variant has been identified in 6/251242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 24, 2022 | The p.R1699W pathogenic mutation (also known as c.5095C>T), located in coding exon 16 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5095. The arginine at codon 1699 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in several ethnically diverse individuals with a personal and/ or family history of breast, ovarian, and prostate cancers (Abkevich V et al. J. Med. Genet. 2004 Jul;41(7):492-507; Zhang S et al. Gynecol. Oncol. 2011 May 1;121(2):353-7; Akbari MR et al. J. Med. Genet. 2011 Nov;48(11):783-6; Dorschner MO et al. Am. J. Hum. Genet. 2013 Oct 3;93(4):631-40; Alemar B et al. PLoS One. 2017 Nov;12:e0187630; Siraj AK et al. Hum Mutat. 2019 06;40:729-733; Millan Catalan O et al. Cancers (Basel). 2019 Aug;11:; Li W et al. J Ovarian Res. 2019 Aug;12:80; Nguyen-Dumont T et al. Int J Cancer. 2020 10;147:2142-2149; Loza P et al. Hered Cancer Clin Pract. 2021 Jan;19:11). This alteration has been classified as pathogenic mutation by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease and mutation co-occurrence (Easton D et al. Am. J. Hum. Genet. 2007;81:873-883; Tavtigian S et al. Hum. Mutat. 2008 Nov;29(11):1342-54). It has also been reported in the compound heterozygous state in a female patient with multiple congenital anomalies, mild intellectual disability, and early onset breast cancer diagnosed at age 23; chromosomal breakage studies were consistent with a Fanconi Anemia-like phenotype, though the patient did not have bone marrow failure (Sawyer SL et al. Cancer Discov. 2015 Feb;5(2):135-42). Functional studies demonstrated significantly reduced transcriptional binding activity and specificity in human cells with p.R1699W (Vallon-Christersson J et al. Hum. Mol. Genet. 2001 Feb 15;10(4):353-60; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90). The p.R1699W mutation introduces a bulky hydrophobic amino acid in the BRCT peptide-binding groove which is critical for tumor suppressor function (Coquelle N et al. Biochemistry. 2011 May 31;50(21):4579-89). Of note, this alteration is also designated as 5214C>T in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Fanconi anemia, complementation group S Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2015 | - - |
| Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This sequence change replaces Arginine with Tryptophan at codon 1699 of the BRCA1 protein (p.Arg1699Trp). The Arginine residue is highly conserved and there is a large physicochemical difference between Arginine and Tryptophan. This variant is present in population databases (ExAC, ESP) at a low frequency (rs55770810). This variant has been reported in individuals with breast and/or ovarian cancer (PMID: 22889855, 21324516, 21356067), and was shown to segregate with breast/ovarian cancer in two families (PMID: 11157798, 17574969). It was also found in trans with a pathogenic BRCA1 variant in an individual affected with Fanconi anemia (PMID: 25472942). The mutation database ClinVar contains an entry for this variant (Variation ID: 55396). Experimental studies have shown that this missense change disrupts BRCA1 binding ability and transcriptional activity (PMID: 21473589, 20516115, 17308087, 23867111). Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be damaging and a multifactorial likelihood algorithm using genetic, in silico, and statistical data has determined that this variant has a very high probability of being deleterious (PMID: 17924331, 21990134). - |
BRCA1-related cancer predisposition Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 07, 2024 | This missense variant replaces arginine with tryptophan at codon 1699 of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant reduces transcriptional activity (PMID: 11157798, 12496476, 17308087, 22889855) and phosphopeptide binding of the BRCA1 protein (PMID: 21473589) and fails to rescue the lethality phenotype in BRCA1-deficient mouse embryonic stem cells (PMID: 23867111). This variant has been reported in many individuals affected with breast and/or ovarian cancer (PMID: 11157798, 17279547, 17574969, 21324516, 22889855, 23289006, 28265380, 30287823) and in the compound heterozygous state in an individual affected with Fanconi anemia (PMID: 25472942). This variant has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000387). In addition, multifactorial likelihood models using health history, in silico, and tumor phenotype data have suggested this variant have a high probability of being pathogenic (PMID: 17279547, 17924331, 21990134). This variant has been identified in 6/251242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Fanconi anemia complementation group A Pathogenic:1
| Pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | May 19, 2015 | - - |
Breast and colorectal cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Arg1699Trp variant was identified in 13 of 2944 proband chromosomes (frequency: 0.004) from German, Finnish and Middle Eastern/North African individuals or families with breast and ovarian cancers (Kuusisto 2011, Laraqui 2014 , Rhiem 2007). Multiple functional assays assessing transcriptional activation in yeast and mammalian cells have found that the variant is temperature sensitive, reducing transactivation, confirmed by segregation analysis of a large pedigree (Vallon-Christersson 2001, Karchin 2007, Worley 2002 , Thouvenot 2016). The variant falls within the BRCT domain and numerous studies have shown that the variant leads to BRCT folding defect thereby reducing the proteolytic and conformational stability of the domain, evidenced by peptide binding assays and protein 3-dimensional structure (Williams 2004, Glover 2006, Shiozaki 2004, Clapperton 2004, Coquelle 2011, Worley 2002 , Carvalho 2014). Classification of UVs using evolutionary conservation, multifactorial likelihood models also define the variant as pathogenic (Abkevich 2004, Mirkovic 2004, Easton 2007, Osorio 2007, Karchin 2007, Gomez Garcia 2009). The variant was identified in a German ovarian cancer patient with a malignant phyllodes tumour of the breast, which account for only 0.3-0.5% of all breast tumours (Rhiem 2007). The variant was also identified in a woman with multiple congenital anomalies consistent with Fanconi anemia-like disorder in biallelism with c. 594_597del; p.(Ser198Argfs*35); having inherited both alleles from her heterozygous parents (Sawyer 2014). The variant was also identified in dbSNP (ID: rs55770810) “With Pathogenic,untested allele”, Clinvitae database (classification pathogenic 7X and likely pathogenic 1X), Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database (classification definitely pathogenic), ARUP Laboratories BRCA Mutations Database (classification definitely pathogenic), the ClinVar database (classification pathogenic, reviewed by an expert panel, submitters: ENIGMA, CIMBA, GeneDx, Invitae, Ambry Genetics, -University of Washington (CSER CC NCGL and Center for Mendelian Genomics, BIC, SCRP (Sharing Clinical Reports Project, derived from Myriad reports); classification likely pathogenic by GeneKor MSA), the BIC database (18x with clinical importance, pending classification), and UMD (6x with a “causal” classification). This variant was identified in the the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles, the genome Aggregation Database (beta, October 19th 2016) in 6 of 246072 chromosomes (freq. 00002), the Exome Aggregation Consortium database (August 8th 2016) in 3 of 120306 chromosomes (freq. 0.00002) in the following populations: Other in 1 of 894 chromosomes (freq. 0.0011), East Asian in 1 of 8594 chromosomes (freq. 0.0001), European (Non-Finnish) in 1 of 66108 chromosomes (freq. 0.00002), , but was not seen African, European (Finnish), Latino and South Asian populations, increasing the likelihood this could be a low frequency benign variant. The p.Arg1699 residue is conserved across mammals and other 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, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Endometrial carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;T;.;.;T;T;.;.;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;M;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;N;.;D;.;.;N;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;D;.;.;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;.;.;D
Polyphen
1.0
.;D;.;.;.;D;.;.;.;D;.
Vest4
MVP
MPC
0.46
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at