Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_007294.4(BRCA1):c.2218G>T(p.Val740Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V740M) has been classified 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]
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
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BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.116905004).
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Jun 01, 2023
The p.V740L variant (also known as c.2218G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2218. The valine at codon 740 is replaced by leucine, an amino acid with highly similar properties. A similar alteration, c.2218G>C, leading to the same amino acid change (p.V740L) has been reported in 1/650 Sicilian breast and/or ovarian cancer patients (Russo A et al. Breast Cancer Res. Treat., 2007 Nov;105:267-76). This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter
curation
University of Washington Department of Laboratory Medicine, University of Washington
Mar 23, 2023
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Mar 07, 2021
Variant summary: BRCA1 c.2218G>T (p.Val740Leu) 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 was absent in 250964 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2218G>T has been reported in the literature in at-least one individual affected with Hereditary Breast Cancer (example, Russo_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Aug 11, 2017
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Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Jan 04, 2024
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 740 of the BRCA1 protein (p.Val740Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 17221156). ClinVar contains an entry for this variant (Variation ID: 185481). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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. -