The variant received 6 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_StrongO2_SupportingO3_Supporting
The NM_001407853.1(BRCA1):c.2T>G (p.Met1?) variant causes a start lost, splice region change involving the alteration of a non-conserved nucleotide. Note: NM_001407853.1 is not a MANE Select or MANE Plus Clinical transcript for BRCA1; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. This is a canonical splice-site variant (loss-of-function). The gene BRCA1 is a tumor suppressor gene (CancerMine: 412 TSG, 22 oncogene, 49 driver citations). The gene BRCA1 is a cancer driver gene (CancerMine: 412 TSG, 22 oncogene, 49 driver citations). The variant allele was found at a cumulative frequency of 0.00000187 (AC=3) in the gnomAD database across 1,602,342 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000301. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004823687: Functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID:8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.C64R: Pathogenic (ClinVar VariationId 54394, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.C64= (synonymous): unknown significance (ClinVar VariationId 867931); p.C64F: unknown significance (ClinVar VariationId 867930) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter).
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):
BRCA1-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
new If you want to explore the variant's impact on the transcript NM_001407853.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
Classification according to ACGS-UK Somatic Oncogenicity v2025
Downstream start codon present; oncogenic/pathogenic variants 5’ of it but ≤10%% N-terminal truncation — O2 supporting (+1); Use caution: splice variant may lead to in-frame exon skipping; Use caution: splice variant may lead to expression of a well-known alternative isoform; Use caution in the presence of multiple transcripts; Gene confirmed as TSG in CancerMine (TSG: 412 citations, oncogene: 22 citations, driver: 49 citations).; Downstream start codon present; oncogenic/pathogenic variants 5’ of it: 96 — verify whether the missing N-terminal region accounts for >10% of the protein
O3Absent or very rare in population
Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000030 — very rare (O3 supporting [+1])
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_001407853.1. You can select a different transcript below to see updated classification assignments.
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
MaveDB functional evidence
MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.
1 abnormal
3 no calibration
4 assays found for this variant.
Clinical calibration: 1 functionally abnormal (PS3), 0 functionally normal (BS3).
Meta-analysis of urn:mavedb:00000097-a-1, urn:mavedb:00000097-b-1, urn:mavedb:00000097-c-1, urn:mavedb:00000097-d-1, urn:mavedb:00000097-e-1 and 21 others