rs61754138
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_000059.4(BRCA2):c.7626G>A(p.Thr2542=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,611,658 control chromosomes in the GnomAD database, including 4 homozygotes. 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. T2542T) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7626G>A | p.Thr2542= | synonymous_variant | 16/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7626G>A | p.Thr2542= | synonymous_variant | 16/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00214 AC: 325AN: 152040Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000582 AC: 146AN: 250786Hom.: 0 AF XY: 0.000457 AC XY: 62AN XY: 135608
GnomAD4 exome AF: 0.000256 AC: 374AN: 1459500Hom.: 3 Cov.: 31 AF XY: 0.000251 AC XY: 182AN XY: 726192
GnomAD4 genome AF: 0.00214 AC: 326AN: 152158Hom.: 1 Cov.: 32 AF XY: 0.00208 AC XY: 155AN XY: 74388
ClinVar
Submissions by phenotype
not specified Benign:8
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Thr2542Thr variant was identified in 4 of 4500 proband chromosomes (frequency: 0.001) from individuals with breast and ovarian cancer (Borg 2010, Morgan 2010, Salazar 2006); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. Myriad classified the variant as a polymorphism (personal communication).The variant was also identified in dbSNP (ID: rs61754138) “With Likely Benign allele”, with a minor allele frequency of 0.0042(21 of 5000 chromosomes in 1000 Genomes Project). In NHLBI Exome Sequencing Project (Exome Variant Server), the variant was found in 27 of 4406 African American chromosomes and was not found in European American chromosomes, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. This variant was identified in the Exome Aggregation Consortium (ExAC) database, released Oct 20th, 2014) in 88 of 120570 chromosomes (frequency: 0.0007299) (or 76 of 10004 African individuals, 8 of 11522 of Latino, 4 of 66482of European (Finnish) chromosomes). The p.Thr2542Thr variant was identified in the ClinVar database (classified as a benign variant by ENIGMA, by Invitae, by GeneDx, Emory Genetics and as a likely benign by Counsyl and Ambry Genetics; as uncertain significance by BIC. In Clinvitae the variant was also identified by EmyClass as benign. BRCA share UMD database identified the variant as likely neutral 16X and co-occurred with BRCA2 pathogenic variants (c.8414_8416delinsC and c.IVS15-2A>T (c.7618-2A>T)) and BRCA1 pathogenic variants (c.211A>G (p.Arg71Gly) and c.IVS16+6T>C (c.4986+6T>C)), increasing the likelihood that the p.Thr2542Thr variant does not have clinical significance. The variant was identified in BIC database 2X with no clinical importance. The p.Thr2542Thr 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, this variant meets our laboratory's criteria to be classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 11, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 30, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 27, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hereditary breast ovarian cancer syndrome Benign:5
Likely benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 22, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Feb 14, 2017 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 17, 2010 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jan 12, 2015 | Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.02033 (African), derived from 1000 genomes (2012-04-30). - |
Likely benign, criteria provided, single submitter | literature only | Counsyl | Jan 02, 2014 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 22, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 02, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2015 | This alteration is classified as 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. - |
not provided Benign:2
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 24, 2021 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 21, 2022 | - - |
Fanconi anemia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at