Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_007294.4(BRCA1):c.2458A>G(p.Lys820Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,613,798 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
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]
Computational evidence support a benign effect (MetaRNN=0.0035055578).
BP6
Variant 17-43093073-T-C is Benign according to our data. Variant chr17-43093073-T-C is described in ClinVar as [Benign]. Clinvar id is 41810.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093073-T-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0089 (1356/152330) while in subpopulation AFR AF= 0.0308 (1279/41578). AF 95% confidence interval is 0.0294. There are 19 homozygotes in gnomad4. There are 649 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
The p.Lys820Glu variant has been identified in 7 of 4428 proband chromosomes (frequency 0.002) in individuals with breast or ovarian cancers (Capanu 2011, Fackenthal 2005, Jalkh 2012); however control chromosomes from healthy individuals were not included in these studies. This variant was identified in dbSNP (rs56082113) and with a frequency of 3% in the African American population from the Exome Variant Server. The variant was also reported 30x in BIC as a variant of unknown clinical importance, and 10x in the UMD as a neutral variant which co-occurred with a known BRCA1 pathogenic mutation (c.3607C>T (p.Arg1203X)). The p.Lys820 residue is not conserved in evolution and the variant amino acid (Glu) is present in macaque and opossum. Furthermore, computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, and two in silico studies have concluded this variant to be neutral or of little clinical significance (Lindor 2012, Tavtigian 2006); however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as benign. -
Nov 01, 2017
GeneKor MSA
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jul 01, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jul 27, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population
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Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:7
Feb 14, 2014
Counsyl
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: literature only
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May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Nov 03, 2014
Michigan Medical Genetics Laboratories, University of Michigan
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Aug 10, 2015
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Benign
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 1 based on posterior probability = 0.00000000000204. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.06098 (African), derived from 1000 genomes (2012-04-30). -
Sep 21, 2015
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jul 24, 2014
Pathway Genomics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: literature only
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Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:5
Feb 19, 2018
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: research
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Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
BRCA1: BP4, BS1, BS2 -
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Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided
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Oct 23, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary cancer-predisposing syndrome Benign:5
Apr 17, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation
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Jan 05, 2016
Vantari Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Dec 06, 2014
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Nov 18, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This alteration is classified as 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. -
May 23, 2018
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Benign:5
Apr 19, 2022
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Feb 14, 2017
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Feb 12, 2014
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Nov 01, 2021
Genetics Program, Instituto Nacional de Cancer
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research
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Breast and/or ovarian cancer Benign:1
Apr 23, 2013
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1
Aug 04, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Benign
Review Status: criteria provided, single submitter