Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5291T>C(p.Leu1764Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
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]
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a domain BRCT 2 (size 99) in uniprot entity BRCA1_HUMAN there are 69 pathogenic changes around while only 15 benign (82%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.917
PP5
Variant 17-43051104-A-G is Pathogenic according to our data. Variant chr17-43051104-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 55510.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43051104-A-G is described in Lovd as [Pathogenic]. Variant chr17-43051104-A-G is described in Lovd as [Pathogenic]. Variant chr17-43051104-A-G is described in Lovd as [Likely_pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5Uncertain:1Other:1
Aug 10, 2015
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation
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 = 0.99 -
Feb 14, 2018
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Aug 08, 2023
All of Us Research Program, National Institutes of Health
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces leucine with proline at codon 1764 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in homology-directed DNA repair, transcription activation, haploid cell proliferation and additional assays (PMID: 30257991, 30209399, 29884841, 27272900, 23867111, 20516115, 20378548, 17308087). This variant has been reported in at least three individuals affected with breast and/or ovarian cancer and in several suspected hereditary breast and ovarian cancer families (PMID: 18824701, 29446198, 30257646, 31076742). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Mar 28, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Pathogenic:2
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:2
Oct 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1764 of the BRCA1 protein (p.Leu1764Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 18824701, 26022348, 29446198, 30257646; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55510). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17305420, 17308087, 20378548, 20516115, 23867111, 27272900, 30209399). For these reasons, this variant has been classified as Pathogenic. -
Jan 31, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: The BRCA1 c.5291T>C (p.Leu1764Pro) variant located in the BRCT domain (via InterPro) involves the alteration of a conserved nucleotide, which 5/5 in silico tools predict a damaging outcome. Multiple functional studies have been performed that support these predictions. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications and databases. The variant of interest has been indicated to cause fold destabilization. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.L1764P variant (also known as c.5291T>C), located in coding exon 19 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5291. The leucine at codon 1764 is replaced by proline, an amino acid with similar properties. The Leu1764 residue is deeply buried in the hydrophobic core of the highly conserved BRCT domain and as such, thermodynamic stability assays indicate that p.L1764P has a destabilizing effect (Rowling PJ et al. J Biol Chem. 2010 Jun; 285(26):20080-7). Functional studies including c-DNA complementation, homologous recombination, yeast-based assays, nuclear localization and solubility assays, and transcription activation assays have all demonstrated deficient function (Carvalho MA et al. Cancer Res. 2007 Feb; 67(4):1494-501; Bouwman P et al. Cancer Discov. 2013 Oct; 3(10):1142-55; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Woods NT et al. NPJ Genom Med 2016 Mar;1; Petitalot A et al. Mol. Cancer Res. 2019 01;17(1):54-69). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -