rs786203358
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate
The NM_000059.4(BRCA2):c.8633A>G(p.Glu2878Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. E2878K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000059.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8633A>G | p.Glu2878Gly | missense_variant, splice_region_variant | Exon 21 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.8264A>G | p.Glu2755Gly | missense_variant, splice_region_variant | Exon 21 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*691A>G | splice_region_variant, non_coding_transcript_exon_variant | Exon 20 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259 | n.*691A>G | 3_prime_UTR_variant | Exon 20 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461796Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727192
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
This variant is denoted BRCA2 c.8633A>G at the cDNA level, p.Glu2878Gly (E2878G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). Using alternate nomenclature, this variant would be defined as BRCA2 8861A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu2878Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu2878Gly occurs at a position that is not conserved and is located within the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Glu2878Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.E2878G variant (also known as c.8633A>G) is located in coding exon 20 of the BRCA2 gene. The glutamic acid at codon 2878 is replaced by glycine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 20. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2878 of the BRCA2 protein (p.Glu2878Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 186963). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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