Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_007294.4(BRCA1):c.121C>G(p.His41Asp) 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. H41R) 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 12 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 chr17-43115738-T-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 17-43115739-G-C is Pathogenic according to our data. Variant chr17-43115739-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 868161.Status of the report is criteria_provided_single_submitter, 1 stars.
Hereditary breast ovarian cancer syndrome Pathogenic:1
Dec 29, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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: 15168169, 16403807, 20103620, 21725363, 23161852, 24489791, 30209399; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 41 of the BRCA1 protein (p.His41Asp). 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: 868161). 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. 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. -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1
Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);