Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6
The NM_007294.4(BRCA1):c.2554C>G(p.Leu852Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L852F) 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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 17-43092977-G-C is Benign according to our data. Variant chr17-43092977-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216656.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1}.
University of Washington Department of Laboratory Medicine, University of Washington
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Mar 18, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The p.L852V variant (also known as c.2554C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 2554. The leucine at codon 852 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:1
Aug 07, 2015
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Hereditary breast ovarian cancer syndromeUncertain:1
Jun 13, 2015
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change replaces leucine with valine at codon 852 of the BRCA1 protein (p.Leu852Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant has not been published in the literature and is not present in population databases. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -