rs1799955
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_000059.4(BRCA2):c.7242A>G(p.Ser2414=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,613,446 control chromosomes in the GnomAD database, including 41,275 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. S2414S) 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 -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7242A>G | p.Ser2414= | synonymous_variant | 14/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7242A>G | p.Ser2414= | synonymous_variant | 14/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.221 AC: 33669AN: 152022Hom.: 3840 Cov.: 32
GnomAD3 exomes AF: 0.225 AC: 56617AN: 251236Hom.: 6718 AF XY: 0.225 AC XY: 30611AN XY: 135782
GnomAD4 exome AF: 0.222 AC: 323719AN: 1461306Hom.: 37436 Cov.: 36 AF XY: 0.222 AC XY: 161245AN XY: 726984
GnomAD4 genome ? AF: 0.221 AC: 33672AN: 152140Hom.: 3839 Cov.: 32 AF XY: 0.225 AC XY: 16723AN XY: 74376
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:11
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 10, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 17, 2011 | - - |
Benign, criteria provided, single submitter | literature only | Counsyl | Jan 02, 2014 | High frequency in a 1kG or ESP population: 21.3 %. - |
Benign, criteria provided, single submitter | clinical testing | GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited | - | - - |
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 0.3864 (Asian), 0.1585 (African), 0.219 (European), derived from 1000 genomes (2012-04-30). - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
not specified Benign:8
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 07, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneKor MSA | Nov 01, 2017 | - - |
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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 23, 2016 | p.Ser2414Ser in exon 14 of BRCA2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 38.47% (3323/8638) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs1799955). - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Ser2414Ser variant was identified globally in 609 of 3040 proband chromosomes (frequency: 0.200) from individuals or families with familial and sporadic breast cancer, and was present in 68 of 364 control chromosomes (frequency: 0.187) from healthy individuals (Akilzhanova 2013, Fackenthal 2012, Jalkh 2012, Toh 2008, Marchina 2010, Saxena 2006, Diez 2003). The variant was identified in dbSNP (ID: rs1799955) “With benign allele”, in the 1000 Genomes Project in 271 of 1165 chromosomes (frequency: 0.2326), HAPMAP-CEU in 22 of 116 chromosomes (frequency: 0.19), HAPMAP-YRI in 25 of 118 chromosomes (frequency: 0.212), HAPMAP-HCB in 29 of 90 chromosomes (frequency: 0.322), NHLBI Exome Sequencing Project (Exome Variant Server) in 1834 of 8600 European American alleles (frequency: 0.2132) and in 915 of 4600 African American alleles (frequency: 0.2077), and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 27219 (heterozygous) and 3228 (homozygous) of 121288 chromosomes (frequency: 0.2244) (or 3988 East Asian individuals, 1740 European(Finnish), 229 Other, 2430 African, 2263 Latino, 3954 South Asian, and 15843 European(Non-Finnish) individuals). The variant was also identified in the Clinvitae database (5X), LOVD, the ClinVar database (classified as a benign variant by multiple submitters with no conflicts; by the Sharing Clinical Reports Project, derived from Myriad reports, BIC, Emory Genetics, Ambry Genetics, GeneDx, and Counsyl), GeneInsight COGR database (1X, classified as “uncertain” by a clinical laboratory), the BIC database (183X with no clinical importance), and in UMD (7X classified as neutral and co-occuring with a pathogenic variant p.Lys82X). The p.Ser2414Ser 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, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Hereditary breast ovarian cancer syndrome Benign:4
Benign, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
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 | Dec 20, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 29, 2016 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 2014 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 31, 2015 | - - |
Fanconi anemia complementation group D1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
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