rs80359139
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000059.4(BRCA2):c.8824G>A(p.Ala2942Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,554 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2942D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8824G>A | p.Ala2942Thr | missense_variant | 22/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8824G>A | p.Ala2942Thr | missense_variant | 22/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250826Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135572
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461554Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727058
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 13, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 23, 2003 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2018 | This variant is denoted BRCA2 c.8824G>A at the cDNA level, p.Ala2942Thr (A2942T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 9052G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2942Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ala2942Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 25, 2020 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 21, 2021 | This missense variant replaces alanine with threonine at codon 2942 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with endometrial carcinoma in the literature (PMID: 26689913). This variant has been identified in 1/250826 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2024 | The p.A2942T variant (also known as c.8824G>A), located in coding exon 21 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8824. The alanine at codon 2942 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 10, 2019 | The BRCA2 c.8824G>A; p.Ala2942Thr variant (rs80359139) is reported with uncertain significance in ClinVar (Variation ID: 52687). This variant is only observed in one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 2942 is highly conserved, but a protein likelihood algorithm specifically designed for BRCA2 missense variants, suggests this variant is tolerated (Karchin 2008). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. REFERENCES Karchin R et al. Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. Cancer Inform. 2008;6:203-16. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2942 of the BRCA2 protein (p.Ala2942Thr). This variant is present in population databases (rs80359139, gnomAD 0.006%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 52687). 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. 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