Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5242G>T(p.Gly1748Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
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 Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.916
PP5
Variant 17-43057087-C-A is Pathogenic according to our data. Variant chr17-43057087-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Other:1
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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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Sep 15, 2011
Sharing Clinical Reports Project (SCRP)
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing
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not provided Pathogenic:1
Jul 19, 2024
GeneDx
Significance: Likely pathogenic
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; Also known as 5361G>T; This variant is associated with the following publications: (PMID: 30209399, 30765603, 32377563, 29884841, 16644204, 28781887, 31131967, 35665744, 10220405, 24389207, 10196224, 9738006, 9811458, 9974970, 11301010, 24845084, 36747619, 31853058) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.G1748C variant (also known as c.5242G>T), located in coding exon 18 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5242. The glycine at codon 1748 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration is functionally deleterious in a haploid cell survival assay as well as a transcription activation assay (Findlay GM et al. Nature, 2018 10;562:217-222; Fernandes VC et al. J Biol Chem 2019 Apr;294(15):5980-5992.). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration is within an alpha-helix and is expected to result in a decrease in structural stability (Ambry internal data). 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Nov 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1748 of the BRCA1 protein (p.Gly1748Cys). 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: 37650). 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, 30765603). This variant disrupts the p.Gly1748 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16644204, 24845084, 28781887, 30209399, 31131967). 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. -