chr13-32370487-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6
The NM_000059.4(BRCA2):c.8417C>T(p.Ser2806Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000114 in 1,613,932 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2806P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8417C>T | p.Ser2806Leu | missense_variant | 19/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8417C>T | p.Ser2806Leu | missense_variant | 19/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152180Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000255 AC: 64AN: 251380Hom.: 0 AF XY: 0.000383 AC XY: 52AN XY: 135862
GnomAD4 exome AF: 0.000120 AC: 175AN: 1461634Hom.: 1 Cov.: 31 AF XY: 0.000184 AC XY: 134AN XY: 727142
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152298Hom.: 1 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74460
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 23, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 25, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2021 | This variant is associated with the following publications: (PMID: 25682074, 25925381, 27978560, 31131967, 29470806, 32531196, 32377563) - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | May 31, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 22, 2016 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 06, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2020 | 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. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 02, 2019 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 24, 2023 | Variant summary: BRCA2 c.8417C>T (p.Ser2806Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251380 control chromosomes, predominantly at a frequency of 0.0021 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.8417C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals undergoing testing for colorectal/breast/ovarian cancer (example, Pearlman_2016, Wong-Brown_2015, Zidan_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Richardson_2021, Hu_2022). These results showed no damaging effect of this variant on homology directed repair (HDR) activity. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). The following publications have been ascertained in the context of this evaluation (PMID: 25682074, 27978560, 28828701, 33609447, 35736817). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at