Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
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 Conflicting classifications of pathogenicity (no stars). 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 9 ACMG points.
PM1
In a helix (size 7) in uniprot entity BRCA1_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) 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 chr17-43063918-T-C is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.886
PP5
Variant 17-43063919-A-G is Pathogenic according to our data. Variant chr17-43063919-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216673.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, not_provided=1}.
Hereditary breast ovarian cancer syndrome Pathogenic:1
Jul 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1703 of the BRCA1 protein (p.Tyr1703His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with peritoneal cancer (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 216673). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 10811118). This variant disrupts the p.Tyr1703 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25948282; Invitae). 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. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. 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/CRST.CRST_101_19) and peritoneal cancer (PMID: 30093976). Other missense variants at this codon, p.Tyr1703Asp and p.Tyr1703Cys, have been reported as likely disease-causing in ClinVar (variation ID: 232915 and 252884). 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. -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1