Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_007294.4(BRCA1):c.5191G>A(p.Glu1731Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,456,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.851
PP5
Variant 17-43063335-C-T is Pathogenic according to our data. Variant chr17-43063335-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91641.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, not_provided=1}.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Other:1
Jul 18, 2011
Sharing Clinical Reports Project (SCRP)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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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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not provided Pathogenic:1
Jan 31, 2020
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell growth (Findlay 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 5310G>A; This variant is associated with the following publications: (PMID: 30209399, 27923043) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.E1731K variant (also known as c.5191G>A), located in coding exon 17 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5191. The glutamic acid at codon 1731 is replaced by lysine, an amino acid with similar properties. 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 10;562:217-222). This alteration was detected in 1/76 individuals of Armenian descent with either a family history of cancer or breast cancer before the age of 40 (Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). This alteration was also observed with an allele frequency of 0 in 7,051 unselected female breast cancer patients and 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Familial cancer of breast Uncertain:1
Jun 12, 2020
Center of Medical Genetics and Primary Health Care
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research
ACMG Guidelines 2015 criteria The BRCA1 variant p.Glu1731Lys is in exon 19 in the BRCT domain (S1642-1736V aa). This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control (Bork et al., 1997). It is found in a mutational hotspot including 34 pathogenic missense, nonsense, and frameshift variants (PM1 Pathogenic Moderate). The allele frequency in GnomAD exomes is 0.0000159 which is less the threshold 0.0001for recessive gene BRCA1, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). 8 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationTaster, REVEL and SIFT versus 3 benign predictions from DEOGEN2, MutationAssessor and PrimateAI support its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was found in a 51-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Variant of Unknown Significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Oct 16, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1731 of the BRCA1 protein (p.Glu1731Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 91641). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -