Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.121C>A variant in BRCA1 is a missense variant predicted to cause substitution of histidine by asparagine at amino acid 41 (p.His41Asn). Reported by two calibrated studies to affect protein function similar to pathogenic control variants (PMID:30209399, 35659930) (PS3 met). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.32, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold ≤0.1) (PP3 met).In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PM2_Supporting, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10601917/MONDO:0700268/092
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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
Significance:Likely pathogenic
Review Status:reviewed by expert panel
Collection Method:curation
The c.121C>A variant in BRCA1 is a missense variant predicted to cause substitution of histidine by asparagine at amino acid 41 (p.His41Asn). Reported by two calibrated studies to affect protein function similar to pathogenic control variants (PMID:30209399, 35659930) (PS3 met). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.32, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold ≤0.1) (PP3 met). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PM2_Supporting, PP3). -
The p.H41N variant (also known as c.121C>A), located in coding exon 2 of the BRCA1 gene, results from a C to A substitution at nucleotide position 121. The histidine at codon 41 is replaced by asparagine, an amino acid with similar properties. One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). Substitutions at this amino acid residue impact E3 ubiquitin ligase activity, however, they have minimal impact on BARD1 binding (Starita LM et al. Genetics, 2015 Jun;200:413-22). Another variant at the same codon, p.H41R (c.122A>G), also non-functional in a high throughput genome editing haploid cell survival assay, has been identified in individuals with features consistent with BRCA1-related cancer predisposition (Whiley PJ et al. PLoS ONE 2014; 9(1):e86836; Findlay GM et al. Nature, 2018 Oct;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 variant is likely to be pathogenic. -
Hereditary breast ovarian cancer syndromePathogenic:1
Oct 25, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 41 of the BRCA1 protein (p.His41Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 409353). 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.His41 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20103620, 21725363, 24489791, 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 providedUncertain:1
May 05, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
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