Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.71G>A(p.Cys24Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. C24?) has been classified as 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 18 ACMG points.
PM1
In a zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) 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 chr17-43124025-ACA-AT is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 17-43124026-C-T is Pathogenic according to our data. Variant chr17-43124026-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43124026-C-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Uncertain:1Other:1
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing
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Dec 20, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:2
Jun 27, 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.71G>A (p.Cys24Tyr) results in a non-conservative amino acid change located in the zinc finger, RING-type domain (IPR001841) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251050 control chromosomes. c.71G>A has been reported in the literature in individuals undergoing genetic testing for a personal and/or family history of breast and/or ovarian cancer (e.g. Machackova_2008, Nakamura_2013, Kwong_2015, Arai_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Functional studies evaluating an impact on protein function showed a damaging effect of this variant on E3 ubiquitin ligase activity, it ability to bind to the BARD1 RING domain, and on homology directed repair (HDR) activity (e.g. Starita_2015, Findlay_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29176636, 30209399, 26187060, 18489799, 24249303, 25823446). ClinVar contains an entry for this variant (Variation ID: 55678). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
May 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 24 of the BRCA1 protein (p.Cys24Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18489799, 24249303, 29176636). This variant is also known as 190G>A. ClinVar contains an entry for this variant (Variation ID: 55678). 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: 25823446, 30209399). This variant disrupts the p.Cys24 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21725363, 23161852, 25823446, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
May 14, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.71G>A (p.Cys24Tyr) variant has been reported in the published literature in individuals with breast cancer (PMID: 24249303 (2015)) and breast and/or ovarian cancer (PMID: 18489799 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). The variant is located in a region that is considered important for protein function and/or structure (PMID: 16403807 (2006), PMID: 20103620 (2010)). Experimental studies demonstrated that this variant was damaging to protein function (PMID: 25823446 (2015), PMID: 30209399 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.C24Y pathogenic mutation (also known as c.71G>A and 190G>A), located in coding exon 1 of the BRCA1 gene, results from a G to A substitution at nucleotide position 71. The cysteine at codon 24 is replaced by tyrosine, an amino acid with highly dissimilar properties. In one study, this alteration was seen in 1 of 1,010 Czech high risk breast and/or ovarian cancer patients (Machackova, E et al. BMC Cancer. 2008 May 20;8:140). This variant is non-functional in multiple assays including BARD1 binding, E3 Ubiquitin Ligase activity and a haploid cell survival assay (Findlay GM. Nature. 2018 10;562(7726):217-222; Starita LM et al. Genetics, 2015 Jun;200:413-22). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Internal structural assessment shows that this alteration disrupts one if the Zn-binding sites of the BRCA1 RING domain (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol., 2001 Oct;8:833-7; Meenakumari, B & Rajkumar, T. Journal of the Indian Institute of Science. 2012 92:3). Multiple pathogenic alterations are located at this position highlighting its sensitivity to amino acid substitution (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. -
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