rs80358745
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):c.5191C>A(p.His1731Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,605,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.5191C>A | p.His1731Asn | missense_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5191C>A | p.His1731Asn | missense_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.4822C>A | p.His1608Asn | missense_variant | 11/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.5191C>A | non_coding_transcript_exon_variant | 10/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152076Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000205 AC: 5AN: 243804Hom.: 0 AF XY: 0.0000152 AC XY: 2AN XY: 131892
GnomAD4 exome AF: 0.0000241 AC: 35AN: 1452964Hom.: 0 Cov.: 45 AF XY: 0.0000249 AC XY: 18AN XY: 722754
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152076Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74276
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:2
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 06, 2012 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Jan 18, 2007 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 16, 2017 | - - |
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 29, 2016 | Variant summary: This c.5191C>A variant affects a non-conserved nucleotide, resulting in amino acid change from His to Asn. 4/4 in-silico tools used predict this variant to be benign. This variant was found in 1/119192 control chromosomes at a frequency of 0.0000084, which does not exceed the maximal expected frequency of a pathogenic allele (0.0007503). This variant has been reported in one ovarian cancer patient without strong evidence of pathogenicity. Multiple clinical labs and a reputable database have classified this variant as having uncertain significance. Because of the limited clinical information and the lack of functional studies, the variant has currently been classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 12, 2024 | The BRCA2 c.5191C>A (p.His1731Asn) variant has been reported in the published literature in individuals affected with ovarian cancer (PMID: 20406939 (2010)). In a large breast cancer association study, the variant was reported in individuals with breast cancer as well as in a reportedly healthy individual (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000045 (5/111278 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 2019 | This variant is associated with the following publications: (PMID: 20406939) - |
Hereditary cancer-predisposing syndrome Benign:3
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 | Jul 26, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 11, 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. - |
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 | May 01, 2023 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at