rs587782137
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_000059.4(BRCA2):c.11G>A(p.Gly4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,038 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 Conflicting classifications of pathogenicity (no stars).
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.11G>A | p.Gly4Glu | missense_variant | Exon 2 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893 | c.-355G>A | 5_prime_UTR_variant | Exon 2 of 27 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.11G>A | non_coding_transcript_exon_variant | Exon 1 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152038Hom.: 0 Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152038Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74252
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces glycine with glutamic acid at codon 4 of the BRCA2 protein (p.Gly4Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141953). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -
Hereditary cancer-predisposing syndrome Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at