Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):c.4245A>G(p.Glu1415Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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 (BayesDel_noAF=-0.53).
BP6
Variant 17-43082516-T-C is Benign according to our data. Variant chr17-43082516-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 55151.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
Synonymous conserved (PhyloP=0.2 with no splicing effect.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:3
Nov 20, 2023
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jun 29, 2017
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Likely benign
Review Status: reviewed by expert panel
Collection Method: curation
Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Jan 01, 2000
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jan 30, 2018
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Benign:4
Aug 19, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Sep 20, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided
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May 18, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is associated with the following publications: (PMID: 12955716, 10686936, 16267036, 25980754) -
Hereditary cancer-predisposing syndrome Benign:3
Nov 20, 2014
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. -
Oct 11, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation
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Aug 03, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not specified Benign:2
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jul 25, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Malignant tumor of breast Benign:1
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
The BRCA1 p.Glu1415Glu variant was identified in 1 of 820 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer, and was not identified in 200 control chromosomes from healthy individuals; the authors call this variant a polymorphism (Diez 2003).The variant was also identified in dbSNP (ID: rs41293453) “With Uncertain significance allele”, NHLBI Exome Sequencing Project (Exome Variant Server), the ClinVar database (classified as an uncertain significance variant by the BIC), the BIC database (3X with unknown clinical importance), and UMD (1X as an unclassified variant).The variant was identified by the Exome Variant Server project in 3 of 13006 European American and African American alleles (frequency: 0.0002), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Glu1415Glu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 although we would lean towards a more benign role for this variant. Thus, this variant is classified as predicted benign. -
BRCA1-related disorder Benign:1
Jul 30, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary breast ovarian cancer syndrome Benign:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter