Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3
The ENST00000357654.9(BRCA1):c.5407G>A(p.Gly1803Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1803C) 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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 16 uncertain in ENST00000357654.9
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43047702-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.745
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
May 26, 2015
The p.G1803S variant (also known as c.5407G>A) is located in coding exon 21 of the BRCA1 gene. The glycine at codon 1803 is replaced by serine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 21. One functional study found that this nucleotide substitution is functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). A close match alteration, BRCA2 c.5408G>C (p.G1803A) is also functional in the cell survival assay, protein folding, binding activity and binding specificity, but has compromised transactivation activity (Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Fernandes VC et al. J. Biol. Chem.. 2019 04;294:5980-5992). This close match, which is expected to behave similarly to this variant, has also been described as having a splice defect (Wappenschmidt B et al. PLoS ONE. 2012 Dec;7:e50800; Ahlborn LB et al. Breast Cancer Res. Treat. 2015 Apr;150:289-98). 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 conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Aug 03, 2020
This missense variant replaces glycine with serine at codon 1803 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jun 01, 2018
Variant summary: BRCA1 c.5407G>A (p.Gly1803Ser) results in a non-conservative amino acid change located in the second C-terminal domain (BRCT domain (IPR001357)) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant alters the first nucleotide of exon 22 and several computational tools predict a significant impact on normal splicing: four predict the variant weakens a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 121582 control chromosomes (in ExAC). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5407G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Wagner 1999). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, however, it does not allow convincing conclusions about the variant effect (Findlay 2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Oct 07, 2018
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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 232037). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 1803 of the BRCA1 protein (p.Gly1803Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1