Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_007294.4(BRCA1):c.*1271T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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]
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43044407-A-G is Pathogenic according to our data. Variant chr17-43044407-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 441519.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=1}.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.53). . Strength limited to SUPPORTING due to the PP5.
The c.*1271T>C variant is located in the 3' untranslated region (3’ UTR) of the BRCA1 gene. This variant results from a T to C substitution 1271 nucleotides downstream of the last translated codon. This nucleotide position is highly conserved in available vertebrate species. This alteration has been detected in a female breast cancer patient who previously tested negative for mutations in the coding exons and splice junctions of BRCA1/2 (Brewster BL et al. Hum Mutat. 2012 Dec;33(12):1665-75). This alteration showed a modest decrease in luciferase activity in multiple human breast cancer cell lines (Brewster BL et al. Hum Mutat. 2012 Dec;33(12):1665-75). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Mar 17, 2025
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant causes a T to C nucleotide substitution in the 3' untranslated region (UTR) of the BRCA1 gene. This variant has been reported in an individual affected with breast cancer (PMID: 22753153). This variant was predicted to induce structural changes to the 3' UTR and impact microRNA binding (PMID: 22753153). A partial reduction of luciferase gene expression was observed when regulated by the BRCA1 3' UTR sequence harboring the variant (PMID: 22753153). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Fanconi anemia, complementation group SPathogenic:1
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:1