rs371278843
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7
The NM_000059.4(BRCA2):c.8421G>A(p.Ser2807=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,613,446 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. S2807S) 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 -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8421G>A | p.Ser2807= | synonymous_variant | 19/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8421G>A | p.Ser2807= | synonymous_variant | 19/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152048Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000342 AC: 86AN: 251344Hom.: 1 AF XY: 0.000464 AC XY: 63AN XY: 135850
GnomAD4 exome AF: 0.000186 AC: 272AN: 1461398Hom.: 4 Cov.: 31 AF XY: 0.000263 AC XY: 191AN XY: 727058
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152048Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74264
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | May 18, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
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 0.0028 (South Asian), derived from ExAC (2014-12-17). - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 22, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 16, 2015 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 31, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 06, 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. - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2014 | 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, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 31, 2018 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
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 | Invitae | Jan 28, 2024 | - - |
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 | May 01, 2023 | - - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Ser2807Ser variant was not identified in the literature. The variant was identified in dbSNP (ID: rs371278843) “With Likely benign allele”, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, the ClinVar database (classified as a benign variant by GeneDx; classified as likely benign by Ambry Genetics), GeneInsight COGR database (1X, classified as “likely benign” by a clinical laboratory), and UMD (1X as a UV variant). This variant was identified in the Exome Variant Server project in 1 of 4406 African American alleles, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015). The variant was also identified in 46 of 16508 individuals from South Asia (frequency: 0.0028) and once in homozygous state, increasing the likelihood this variant does not have clinical significance. It was also identified in one East Asian and one African individual, increasing the likelihood this could be a low frequency benign variant in certain populations of origin. The p.Ser2807Ser 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. It should be noted that another variant at the same position (c.8421G>T, p.Ser2807Ser) did not show splicing aberration and classified as Class 2, likely not pathogenic, according to the IARC 5 class system (Thomassen 2012). In summary, based on the above information this variant is classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at