Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_007294.4(BRCA1):c.3028C>T(p.Pro1010Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. P1010T) 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
The p.P1010S variant (also known as c.3028C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3028. The proline at codon 1010 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a breast cancer patient diagnosed at age 29; however, p.P1010S did not significantly impact BRCA1 function in a yeast recombination assay (Caligo MA et al. Hum Mutat, 2009 Jan;30:123-33). This amino acid position is not well conserved in available 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. -
Mar 23, 2023
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). -
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:1
Sep 26, 2015
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group SUncertain:1
Dec 16, 2019
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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not providedUncertain:1
Dec 15, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The BRCA1 c.3028C>T (p.Pro1010Ser) variant has been reported in the published literature in an individual with breast cancer (PMID: 18680205 (2009)). This variant has also been reported to have no significant effect on BRCA1 homologous repair activity in a yeast-based system (PMID: 18680205 (2009)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Hereditary breast ovarian cancer syndromeUncertain:1
Jul 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1010 of the BRCA1 protein (p.Pro1010Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 18680205). ClinVar contains an entry for this variant (Variation ID: 374941). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 18680205). 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. -