17-43094139-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):c.1392C>T(p.Thr464=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. T464T) has been classified as Likely benign.
Frequency
Consequence
NM_007294.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.1392C>T | p.Thr464= | synonymous_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.1392C>T | p.Thr464= | synonymous_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000131 AC: 33AN: 251118Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135724
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461750Hom.: 0 Cov.: 34 AF XY: 0.0000344 AC XY: 25AN XY: 727182
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74420
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:3
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 29, 2017 | Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.001 (East Asian), derived from ExAC (2014-12-17). - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | May 26, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2018 | This variant is associated with the following publications: (PMID: 25337278, 27257965, 16267036, 10340909, 30702160) - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 25, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 26, 2018 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 28, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 05, 2014 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 03, 2021 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 10, 2019 | Variant summary: BRCA1 c.1392C>T results in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 301874 control chromosomes, predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1392C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, predominantly of Chinese ethnicity (Bhaskaran_2019, Judkins_2005, Sun_2014, Tang_1999, Zhong_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions from clinical diagnostic laboratories and an expert panel cite the variant predominantly as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. - |
Breast neoplasm Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University | Nov 01, 2015 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Thr464= variant was identified in 9 of 111520 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer (Judkins 2005, Tang 1999). The variant was also identified in dbSNP (ID: rs533802049) as With other allele, ClinVar (classified as benign by Enigma, GeneDx; classified as likely benign by Ambry Genetics, Invitae), Clinvitae (conflicting interpretations of pathogenicity by ClinVar; likely benign by Invitae), Genesight-COGR (benign, likely benign, uncertain significance), UMD-LSDB (1X as class3), Zhejiang Colon Cancer Database (1X), databases. The variant was not identified in LOVD 3.0, BIC Database, ARUP Laboratories, databases. The variant was identified in control databases in 31 of 276894 chromosomes at a frequency of 0.000112 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include EastAsian in 31 of 18866 chromosomes (freq: 0.0016), while the variant was not observed in the African, Other, Latino, EuropeanNon-Finnish, AshkenaziJewish, EuropeanFinnish, and SouthAsian populations. The p.Thr464= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at