Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5213G>A(p.Gly1738Glu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1738R) has been classified as Likely 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 16 ACMG points.
PM1
In a mutagenesis_site Abolishes interaction with BRIP1. (size 0) in uniprot entity BRCA1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43057117-C-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.923
PP5
Variant 17-43057116-C-T is Pathogenic according to our data. Variant chr17-43057116-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43057116-C-T is described in Lovd as [Pathogenic]. Variant chr17-43057116-C-T is described in Lovd as [Pathogenic]. Variant chr17-43057116-C-T is described in Lovd as [Likely_pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7Uncertain:1Other:1
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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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Jul 04, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
A 46-year-old female whit metastatic unilateral breast cancer (IDC). she has history of breast cancer in her second degree relatives (her paternal aunts). -
Aug 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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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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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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Jul 01, 2015
Department of Medical Genetics, Oslo University Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Feb 02, 2022
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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May 27, 2024
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
PP3; PS3; PP1_Strong; PM2_Supporting -
Aug 26, 2022
BRCAlab, Lund University
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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not provided Pathogenic:2
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Mar 13, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces glycine with glutamic acid at codon 1738 of the BRCA1 protein. Computational and in silico lines of evidence consistently support a deleterious effect on the function of the gene or gene product (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant protein is defective in assays for protease sensitivity, peptide binding, phospho-peptide specificity, transcriptional activation, and a haploid cell proliferation (PMID: 10811118, 11157798, 20516115, 30209399). This variant has been reported in individuals and families affected breast cancer and ovarian cancer (PMID: 11157798, 18465347, 21918854, 23113073, 30678073, 23113073). It has been shown that this variant segregates with breast cancer in two families, including one family with five breast cancer affected members across three generations (PMID: 23113073). Variant results in a different missense amino acid change in same location as a previously established pathogenic variant (p.Gly1738Arg). 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 Pathogenic. -
Sep 03, 2024
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.G1738E variant (also known as c.5213G>A), located in coding exon 18 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5213. The glycine at codon 1738 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Keshavarzi F et al. Fam Cancer, 2012 Mar;11:57-67). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Aug 23, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.5213G>A (p.Gly1738Glu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.5213G>A has been reported in the literature in several individuals and families affected with Hereditary Breast and Ovarian Cancer (Keshavarzi_2012, Nielsen_2016). These data indicate that the variant is very likely to be associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated protein folding defect, compromised phosphopeptide binding, and decreased transcriptional activity in yeast and human cells (Hayes_2000, Lee_2010). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and they classified the variant as pathogenic (2x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Sep 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1738 of the BRCA1 protein (p.Gly1738Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 18465347, 21918854, 23113073). ClinVar contains an entry for this variant (Variation ID: 55462). 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: 10811118, 11157798, 20516115). This variant disrupts the p.Gly1738 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21990134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -