Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_007294.4(BRCA1):āc.4417T>Cā(p.Ser1473Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. S1473S) 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 Uncertain_significance. Variant got 3 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_007294.4
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.36080033).
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Jul 13, 2023
The p.S1473P variant (also known as c.4417T>C), located in coding exon 12 of the BRCA1 gene, results from a T to C substitution at nucleotide position 4417. The serine at codon 1473 is replaced by proline, an amino acid with similar properties. In one study, this variant was reported in two families with Hereditary Breast and Ovarian Cancer syndrome; however, this variant demonstrated intact transcriptional activity comparable to the wild-type BRCA1 protein in a transcription activation assay (Quiles F et al. PLoS ONE 2013 April; 8(4):e61302). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited 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
Nov 16, 2022
This missense variant replaces serine with proline at codon 1473 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA1 function in a transcription activation assay (PMID: 23613828). This variant has been reported in an individual suspected of hereditary breast and ovarian cancer (PMID: 23613828). A multifactorial analysis has reported family history, tumor pathology and co-segregation likelihood ratios for pathogenicity of 0.14, 0.003 and 1.195, respectively (PMID: 34597585). 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 provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Dec 16, 2019
Observed in individuals suspected of Hereditary Breast and Ovarian Cancer Syndrome (Quiles 2013); Published functional studies demonstrate no damaging effect: Transcriptional activation activity similar to wild-type (Quiles 2013); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as c.4536T>C; This variant is associated with the following publications: (PMID: 23613828) -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Sep 01, 2023
This missense change has been observed in individual(s) with clinical features of Hereditary Breast and Ovarian Cancer Syndrome (PMID: 23613828). 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 have shown that this missense change does not substantially affect BRCA1 function (PMID: 23613828). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 91630). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1473 of the BRCA1 protein (p.Ser1473Pro). -
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter
clinical testing
MGZ Medical Genetics Center
Feb 09, 2024
ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP -