rs80358820
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000059.4(BRCA2):c.5882G>A(p.Ser1961Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. S1961I) 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 -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.5882G>A | p.Ser1961Asn | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5882G>A | p.Ser1961Asn | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250986Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135800
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461710Hom.: 0 Cov.: 45 AF XY: 0.00000275 AC XY: 2AN XY: 727152
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74304
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:2
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 12, 2012 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 04, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Jun 20, 2002 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign: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). - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 19, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 21, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 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. - |
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 01, 2023 | In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 23683081 (2013), 16758124 (2006), 15937982 (2005)). Additionally, the variant has been characterized as being a variant of uncertain significance in a multifactorial likelihood study (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.000046 (1/21644 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. - |
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 | May 14, 2019 | This variant is associated with the following publications: (PMID: 23683081, 16758124, 15937982) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 13, 2023 | Variant summary: BRCA2 c.5882G>A (p.Ser1961Asn) results in a conservative amino acid change located in the BRCA2 repeat region, between the repeats BRC6 and BRC7 (IPR002093) of 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 8e-06 in 250986 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5882G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Blay_2013, Infante_2006, Velasco_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.3331_3334delCAAG, p.Gln1111fsX5 in the BIC database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=6) and VUS (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at