13-32379344-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000059.4(BRCA2):c.8782G>T(p.Ala2928Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8782G>T | p.Ala2928Ser | missense_variant | Exon 22 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.8413G>T | p.Ala2805Ser | missense_variant | Exon 22 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*840G>T | non_coding_transcript_exon_variant | Exon 21 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259 | n.*840G>T | 3_prime_UTR_variant | Exon 21 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461524Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727060
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
BRCA2-related cancer predisposition Uncertain:2
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This missense variant replaces alanine with serine at codon 2928 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31394 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. -
Hereditary cancer-predisposing syndrome Uncertain:2
This missense variant replaces alanine with serine at codon 2928 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.102 and 1.318, respectively (PMID: 31131967). This variant has been identified in 1/31394 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. -
The p.A2928S variant (also known as c.8782G>T), located in coding exon 21 of the BRCA2 gene, results from a G to T substitution at nucleotide position 8782. The alanine at codon 2928 is replaced by serine, an amino acid with similar properties. This amino acid position is highly 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 provided Uncertain:1
This variant is denoted BRCA2 c.8782G>T at the cDNA level, p.Ala2928Ser (A2928S) at the protein level, and results in the change of an Alanine to a Serine (GCC>TCC). This variant, also known as BRCA2 9010G>T using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2928Ser 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 Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala2928Ser occurs at a position that is conserved among mammals and is located in 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 information, it is unclear whether BRCA2 Ala2928Ser is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Familial cancer of breast Uncertain:1
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Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2928 of the BRCA2 protein (p.Ala2928Ser). This variant is present in population databases (rs587781762, gnomAD 0.007%). 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: 141459). 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%. 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