rs56337919
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BP6_Very_Strong
The NM_000059.4(BRCA2):c.3839A>T(p.Asp1280Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,558,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1280G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.3839A>T | p.Asp1280Val | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.3839A>T | p.Asp1280Val | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152238Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000283 AC: 6AN: 212168Hom.: 0 AF XY: 0.0000433 AC XY: 5AN XY: 115602
GnomAD4 exome AF: 0.0000512 AC: 72AN: 1405794Hom.: 0 Cov.: 34 AF XY: 0.0000517 AC XY: 36AN XY: 696450
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74382
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:4
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 22, 2009 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Benign, criteria provided, single submitter | clinical testing | Counsyl | Dec 01, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000286 - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 17, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 31, 2020 | Variant summary: BRCA2 c.3839A>T (p.Asp1280Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 212168 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3839A>T has been reported in the literature in sequencing studies of individuals with high risk breast cancer as well as in an unaffected individual (Lu_2012, Carney_2010) in addition to sequencing studies of patients undergoing cancer screening for varied indications (example, Easton_2007, DeLeeneer_2008, Seymour_2008, Hartman_2001, Machackova_2019). These reports do not provide unequivocal conclusions regarding the association of this variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.66dupA, p.Glu23fsX18), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign (n=4)/likely benign(n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. We have not identified any evidence supporting an actionable outcome in over 5 years since its initial classification by our laboratory. Based on the evidence outlined above, and the predominant consensus in the field, the variant was classified as benign. - |
Hereditary cancer-predisposing syndrome Benign:3
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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 28, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 02, 2016 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24323938, 11698567, 17924331, 21990134) - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 15, 2017 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at