rs80358817
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):āc.5869A>Gā(p.Ile1957Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,864 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. I1957M) has been classified as Likely 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.5869A>G | p.Ile1957Val | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5869A>G | p.Ile1957Val | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250986Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135784
GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461686Hom.: 0 Cov.: 44 AF XY: 0.0000564 AC XY: 41AN XY: 727144
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74344
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Ile1957Val variant was identified in the literature in hereditary breast and ovarian cancer patients, however the frequency of this variant in an affected population was not provided (Schenkel_2016_PMID:27376475; Hondow_2011_PMID:21702907). The variant was identified in dbSNP (ID: rs80358817), ClinVar (classified as likely benign 2x and uncertain significance 7x; associated condition is hereditary breast and ovarian cancer syndrome), and Cosmic (confirmed somatically in a breast carcinoma tissue with a FATHMM prediction score of 0.10, neutral). The variant was identified in control databases in 5 of 282390 chromosomes at a frequency of 0.000018 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 5 of 128968 chromosomes (freq: 0.000039), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Ile1957 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence; however three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the creation of a new 5Ć¢ā¬Å”ĆāĆĀ“ splice site near the site of variation. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 19, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2017 | - - |
not specified Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 19, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 20, 2019 | The BRCA2 c.5869A>G; p.Ile1957Val variant (rs80358817) has been reported in at least one individual affected with hereditary breast and ovarian cancer (Schenkel 2016). It is reported as a variant of unknown significance by several laboratories in ClinVar (Variation ID: 51957) and observed in the European population at an overall frequency of 0.004% (5/126572) in the Genome Aggregation Database. The isoleucine at codon 1957 and computational algorithms (PolyPhen-2, SIFT) predict that this variant does not affect protein structure and/or function. Splice predictors (Alamut v.2.11) predict that this variant creates a cryptic donor splice site, but functional mRNA studies are necessary to determine the effect of this variant on splicing. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Schenkel L et al. Clinical Next-Generation Sequencing Pipeline Outperforms a Combined Approach Using Sanger Sequencing and Multiplex Ligation-Dependent Probe Amplification in Targeted Gene Panel Analysis. J Mol Diagn. 2016 Sep;18(5):657-667. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 16, 2019 | Variant summary: BRCA2 c.5869A>G (p.Ile1957Val) 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. Several computational tools predict that this variant may have an impact on normal splicing by creating a 5' cryptic donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 250986 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5869A>G has been reported in the literature, without strong evidence for causality (Schenkel_2016). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2x likely benign and 5x uncertain significance). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
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 | Ambry Genetics | Apr 26, 2021 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 11, 2016 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 23, 2003 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 21, 2015 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1957 of the BRCA2 protein (p.Ile1957Val). This variant is present in population databases (rs80358817, gnomAD 0.004%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 21702907, 27376475, 34326862). ClinVar contains an entry for this variant (Variation ID: 51957). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at