Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_007294.4(BRCA1):c.3587C>A(p.Thr1196Lys) 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. T1196S) has been classified as Uncertain significance.
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: Likely_benign. The variant received -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.184823).
BP6
Variant 17-43091944-G-T is Benign according to our data. Variant chr17-43091944-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 54925.
The p.T1196K variant (also known as c.3587C>A and 3706C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 3587. The threonine at codon 1196 is replaced by lysine, an amino acid with some similar properties. This alteration has been reported as a variant of unknown significance based on mammalian conservation and chemical characteristics of the amino acid substitution (Burk-Herrick A et al. Mamm Genome. 2006 Mar; 17(3):257-70). This amino acid position is not 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.
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
Feb 15, 1997
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
not providedUncertain:1
May 26, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3706C>A
Hereditary breast ovarian cancer syndromeUncertain:1
Jul 05, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 9333265). ClinVar contains an entry for this variant (Variation ID: 54925). 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. 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. This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 1196 of the BRCA1 protein (p.Thr1196Lys).