chr17-43057069-C-A
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5260G>T(p.Glu1754*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E1754E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007294.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Fanconi anemia, complementation group SInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 4Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251494 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461786Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727196 show subpopulations
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3
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Variant allele predicted to encode a truncated non-functional protein. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. Truncating variants in BRCA1 are known to be pathogenic. This particular truncation has been found in individuals affected with breast cancer with a family history of breast ovarian cancer  (PMID: 12497638, 25863477). This sequence change creates a premature translational stop signal at codon 1754 (p.Glu1754*). It is expected to result in an absent or disrupted protein product. -
This sequence change creates a premature translational stop signal at codon 5260 of the BRCA1 protein. It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This particular variant has been described in the mutation database ClinVar (Variation ID: 55489) -
not provided Pathogenic:1
The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.E1754* pathogenic mutation (also known as c.5260G>T), located in coding exon 18 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5260. This changes the amino acid from a glutamic acid to a stop codon within coding exon 18. This alteration has been identified in multiple families with breast and/or ovarian cancer (Valarmathi MT et al. Hum Mutat, 2003 Jan;21:98-9; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Lesueur F et al. Front Oncol, 2018 Oct;8:490; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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 10;562:217-222). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note this alteration is also described in the literature as 5379G>T. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at