Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2T>C(p.Met1?) variant causes a start lost 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 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]
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
Our verdict: Pathogenic. The variant received 20 ACMG points.
PVS1
Start lost variant, next in-frame start position is after 34 pathogenic variants. Next in-frame start position is after 18 codons. Genomic position: 43124045. Lost 0.009 part of the original CDS.
PS1
Another start lost variant in NM_007294.4 (BRCA1) was described as [Pathogenic] in ClinVar
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43124095-A-G is Pathogenic according to our data. Variant chr17-43124095-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 54745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
BRCA1
NM_007294.4
MANE Select
c.2T>C
p.Met1?
start_lost
Exon 2 of 23
NP_009225.1
BRCA1
NM_001407581.1
c.2T>C
p.Met1?
start_lost
Exon 2 of 24
NP_001394510.1
BRCA1
NM_001407582.1
c.2T>C
p.Met1?
start_lost
Exon 2 of 24
NP_001394511.1
Ensembl Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
BRCA1
ENST00000357654.9
TSL:1 MANE Select
c.2T>C
p.Met1?
start_lost
Exon 2 of 23
ENSP00000350283.3
BRCA1
ENST00000471181.7
TSL:1
c.2T>C
p.Met1?
start_lost
Exon 2 of 24
ENSP00000418960.2
BRCA1
ENST00000470026.6
TSL:1
c.2T>C
p.Met1?
start_lost
Exon 2 of 23
ENSP00000419274.2
Frequencies
GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:3
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Aug 17, 2017
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the BRCA1 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 05;39(5):593-620). This alteration is predicted to result in the loss of the first 17 amino acids of BRCA1. These RING domain residues comprise a significant portion of the N-helix of the four helix bundle that is crucial for BARD1/BRCA1 dimerization which, in turn, is responsible for their mutual stability, appropriate nuclear localization, and ubiquitin ligase activity (Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8(10): 833-7; Brzovic PS et al. J. Biol. Chem. 2001 Nov;276(44):41399-406; Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100(10):5646-51). 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(7726):217-222). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Hereditary breast ovarian cancer syndromePathogenic:1
May 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change affects the initiator methionine of the BRCA1 mRNA. The next in-frame methionine is located at codon 18. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 54745). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects BRCA1 function (PMID: 21922593, 30209399). For these reasons, this variant has been classified as Pathogenic.