Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5107T>G(p.Tyr1703Asp) 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 Likely pathogenic (★★). 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 Pathogenic. Variant got 16 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, 0.897
PP5
Variant 17-43063919-A-C is Pathogenic according to our data. Variant chr17-43063919-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Hereditary breast ovarian cancer syndrome Pathogenic:2
Dec 14, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.5107T>G (p.Tyr1703Asp) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251312 control chromosomes. To our knowledge, no occurrence of c.5107T>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of homology directed repair (HDR) activity in a high throughput assay measuring cellular fitness in a haploid cell line whose survival is dependent on intact BRCA1 function (Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG PS3) as sufficient weightage for categorization as likely pathogenic (Tavtigian_2018). The following publication have been ascertained in the context of this evaluation (PMID: 30209399). ClinVar contains an entry for this variant (Variation ID: 252884). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Mar 16, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. ClinVar contains an entry for this variant (Variation ID: 252884). 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, 30209399; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1703 of the BRCA1 protein (p.Tyr1703Asp). -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Uncertain:1
Feb 20, 2009
Sharing Clinical Reports Project (SCRP)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Feb 26, 2024
Brotman Baty Institute, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: in vitro
The c.5107 T>G/p.Tyr1703Asp variant in the BRCA1 gene was identified in an individual in the Brotman Baty Institute Clinical Variant Database (BBI-CVD) database who underwent clinical genetic testing for a family history of early onset breast cancer. It was also identified in this individual's affected sister, who was diagnosed with breast cancer in her early 40s. To our knowledge, there are no reports of this variant in the literature in association with disease. This variant is absent in large population databases including the Genome Aggregation Database. This variant is located within the BRCT domain and is predicted to impact protein function (BayeDel >=0.28). It has been reported by one calibrated study to affect protein function similar to pathogenic control variants (Findlay et al. 2018). Using the ClinGen ENIGMA BRCA1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.1.0, this variant was classified as Likely Pathogenic (PS3_Strong, PM2_Supporting, PP3_Supporting, PP4_Supporting). -