Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.3739G>A(p.Val1247Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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=0.017272323).
BP6
Variant 17-43091792-C-T is Benign according to our data. Variant chr17-43091792-C-T is described in ClinVar as [Benign]. Clinvar id is 54985.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091792-C-T is described in Lovd as [Benign]. Variant chr17-43091792-C-T is described in Lovd as [Likely_benign].
Genetic Services Laboratory, University of Chicago
Aug 29, 2022
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Benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Mar 26, 2019
Variant summary: BRCA1 c.3739G>A (p.Val1247Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 282924 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.001 in the gnomAD database. This frequency is about the same that is expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.001), suggesting that the variant might be a benign polymorphism found primarily in populations of East Asian origin. c.3739G>A has been reported in the literature in individuals, mostly of East Asian origin, affected with breast or ovarian cancer, however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5213_5216delCTTA (p.Thr1738fsX2) in the UMD BRCA1 database), providing supporting evidence for a benign role. In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, predicted this variant to be likely neutral (Easton 2007 and Lindor 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (3x) while the expert panel ruled on its classification as benign (1x). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided
clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
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Benign, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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Benign, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Aug 15, 2023
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Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:3
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
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Benign, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
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Benign, 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 1 based on posterior probability = 0.00000251 -
Benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Feb 03, 2010
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Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jan 02, 2022
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Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 18, 2014
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. -
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Feb 03, 2021
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not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Dec 23, 2020
This variant is associated with the following publications: (PMID: 27153395, 24916970, 25682074, 17924331, 15385441, 18824701, 15235020, 25337278, 26689913, 16826315, 27157322, 22753008, 18779604, 21990134, 27907908, 16267036, 10923033, 23704879, 33087888) -
Uncertain significance, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
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Familial cancer of breast Benign:1
Likely benign, no assertion criteria provided
literature only
Center for Precision Medicine, Meizhou People's Hospital
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BRCA1-related disorder Benign:1
Benign, no assertion criteria provided
clinical testing
PreventionGenetics, part of Exact Sciences
Mar 26, 2019
This variant is classified as 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