Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5339T>G(p.Leu1780Arg) 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1780V) 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: Pathogenic. The variant received 16 ACMG points.
PM1
In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 85 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43049188-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.888
PP5
Variant 17-43049188-A-C is Pathogenic according to our data. Variant chr17-43049188-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 96949.Status of the report is reviewed_by_expert_panel, 3 stars.
Hereditary breast ovarian cancer syndromePathogenic:2
Oct 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1780 of the BRCA1 protein (p.Leu1780Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 96949). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). This variant disrupts the p.Leu1780Pro amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28364669; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Jan 20, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: BRCA1 c.5339T>G (p.Leu1780Arg) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251430 control chromosomes. To our knowledge, no occurrence of c.5339T>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. A different variant affecting the same codon has been classified as pathogenic by our lab (c.5339T>C, p.Leu1780Pro), supporting the critical relevance of codon 1780 to BRCA1 protein function. At least one experimental study reports experimental evidence evaluating an impact on protein function and showed this variant to be non-functional in a homology directed repair (HDR) assay (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publication has been ascertained in the context of this evaluation (PMID: 30209399). ClinVar contains an entry for this variant (Variation ID: 96949). Based on the evidence outlined above, the variant was classified as pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:2
May 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Jan 03, 2017
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
The p.L1780R variant (also known as c.5339T>G), located in coding exon 20 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5339. The leucine at codon 1780 is replaced by arginine, an amino acid with dissimilar properties. One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Wu Q et al. Mol. Cell, 2016 Feb;61:434-448). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -