rs80356992
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4612C>T(p.Gln1538Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1538Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007294.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.4612C>T | p.Gln1538Ter | stop_gained | 14/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.4612C>T | p.Gln1538Ter | stop_gained | 14/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 22, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 02, 2019 | This variant causes the premature termination of BRCA1 protein synthesis. It has been reported in in affected individuals with breast and/or ovarian cancer in the published literature (PMIDs: 9452076 (1998), 11920621 (2002), 25151137 (2015), 29339979 (2018) and 29470806 (2018)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4731C>T; This variant is associated with the following publications: (PMID: 21720365, 9452076, 11920621, 25525159, 26187060, 24578176, 25151137, 27221827, 19298662, 29339979, 30787465, 29470806, 31214711, 32410793, 29446198, 34917121, 30720243, 31825140, 30322717, 33948387) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2021 | The p.Q1538* pathogenic mutation (also known as c.4612C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4612. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This mutation has been reported in multiple individuals and families with hereditary breast and ovarian cancer (HBOC) (Tartaglini E et al. Hum. Mutat., 1998;Suppl 1:S163-6; De Leon Matsuda ML et al. Int. J. Cancer, 2002 Apr;98:596-603; Young SR et al. BMC Cancer, 2009 Mar;9:86; Guan Y et al. Fam Cancer, 2015 Mar;14:9-18; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Wang N et al. Chin J Cancer Res, 2020 Apr;32:149-162). This mutation has also been reported with a carrier frequency of 0.00013 in 7636 unselected prostate cancer patients and absent in 12366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). Of note, this alteration is also designated as 4731C>T and Q1538X in published literature. 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change creates a premature translational stop signal (p.Gln1538*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 9452076, 11920621, 25151137, 29446198, 29470806). This variant is also known as 4731C>T. ClinVar contains an entry for this variant (Variation ID: 55239). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 12, 2020 | Variant summary: BRCA1 c.4612C>T (p.Gln1538X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251362 control chromosomes (gnomAD). c.4612C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Rebbeck_2018, DeLeonMatsuda_2002, Singh_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) including one expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at