Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_007294.4(BRCA1):c.5107T>C(p.Tyr1703His) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1703C) has been classified 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 Likely_pathogenic. Variant got 8 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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 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;
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr17-43063918-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 232915.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Likely_pathogenic=2}.
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.886
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Sep 20, 2021
This missense variant replaces a conserved tyrosine with histidine at codon 1703 in the BRCT domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in a haploid cell proliferation assay and in a yeast transcription activation screen (PMID: 10811118, 30209399). This variant has been reported in one individual each affected with ovarian cancer (doi:10.4103%2FCRST.CRST_101_19) and peritoneal cancer (PMID: 30093976). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
May 14, 2015
In summary, this is a novel missense change that may impact protein function and cause disease. However, since there is insufficient evidence at this time to prove that conclusively, it has been classified as a Variant of Uncertain Significance. A different amino acid substitution at this codon (c.5108A>C, p.Tyr1703Ser) has been reported in an individual suspected of having breast and/or ovarian cancer. Functional analysis of this missense change shows that it abolishes the transcriptional activity of BRCA1 (PMID: 23613828). However, the clinical significance of this finding is uncertain and does not contribute to the classification of the p.Tyr1703His change. 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 disruptive. Also, experimental studies have shown that this missense change disrupts the transcriptional transactivation activity of the BRCA1 protein (PMID: 10811118). This variant has not been reported in affected individuals in the literature, and is not present in population databases. This variant has also not been reported in affected patients in the Breast Cancer Information Core database (PMID: 10923033) and the Universal Mutation Database (PMID: 22144684). This sequence change replaces tyrosine with histidine at codon 1703 of the BRCA1 protein (p.Tyr1703His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1