Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_007294.4(BRCA1):āc.5561T>Cā(p.Leu1854Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1854L) 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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a domain BRCT 2 (size 99) in uniprot entity BRCA1_HUMAN there are 69 pathogenic changes around while only 15 benign (82%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.912
PP5
Variant 17-43045709-A-G is Pathogenic according to our data. Variant chr17-43045709-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55631.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, not_provided=1}.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Other:1
Dec 23, 2003
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Feb 07, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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not provided Pathogenic:2
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Dec 07, 2023
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5680T>C; This variant is associated with the following publications: (PMID: 30765603, 35196514, 29884841, 32377563, 35918668, 20516115, 28781887, 30209399, 35665744, 25348405, 31131967) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.L1854P variant (also known as c.5561T>C), located in coding exon 22 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5561. The leucine at codon 1854 is replaced by proline, an amino acid with similar properties. Protein functional assays have demonstrated that this alteration is non-functional (Findlay GM et al. Nature, 2018 10;562:217-222; Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Adamovich AI et al. Am J Hum Genet 2022 Apr;109(4):618-630). This alteration was also detected in 1/1664 individuals diagnosed with breast and/or ovarian cancer (Zhang Y et al. BMC Cancer, 2022 Aug;22:842).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Familial cancer of breast Uncertain:1
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Center for Precision Medicine, Meizhou People's Hospital
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only
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Hereditary breast ovarian cancer syndrome Uncertain:1
Dec 17, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 20516115, 30209399). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 55631). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1854 of the BRCA1 protein (p.Leu1854Pro). -