chr13-32332343-A-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):āc.865A>Gā(p.Asn289Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,445,970 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N289H) has been classified as Benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.865A>G | p.Asn289Asp | missense_variant | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.865A>G | p.Asn289Asp | missense_variant | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000125 AC: 3AN: 239502Hom.: 0 AF XY: 0.0000155 AC XY: 2AN XY: 129342
GnomAD4 exome AF: 0.00000415 AC: 6AN: 1445970Hom.: 0 Cov.: 30 AF XY: 0.00000695 AC XY: 5AN XY: 719086
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2020 | This variant is associated with the following publications: (PMID: 24853695, 26483394, 25896959, 24504028, 29258903, 28814288, 27165220, 28324225) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 29, 2023 | The frequency of this variant in the general population, 0.000027 (3/110406 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has been observed to co-occur with the BRCA2 c.5864C>A (p.Ser1955*) pathogenic variant in multiple individuals (PMID: 25186627 (2015)) suggesting the c.865A>G (p.Asn289Asp) variant is not the primary cause of disease. However, this variant by itself has also been reported in individuals with breast/ovarian cancer (PMIDs: 32438681 (2020), 32284662 (2019), 28324225 (2017), 27165220 (2016), 25896959 (2015), 24504028 (2014)), and pancreatic cancer (PMID: 26483394 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 20, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2018 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 16, 2021 | - - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 03, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 19, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jul 02, 2008 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2023 | Variant summary: BRCA2 c.865A>G (p.Asn289Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 314878 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.865A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or other types of cancer (Wappenschmidt_2006, Cunningham_2014, Yang _2015, DArgenio_2015, Hu_2015, Tung_2015, Meisel_2017, Santonocito_2020, de Oliveira_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with one specific pathogenic variant (BRCA2 c.5864C>A, p.Ser1955X) have been reported in patients, providing supporting evidence for a benign role (kConFab data, BIC data, Internal data, Tung_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24504028, 25896959, 26483394, 28324225, 36243179, 32438681, 25186627, 26535628, 35534704). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=5) and likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. - |
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 | Feb 07, 2021 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at