13-32340372-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000059.4(BRCA2):āc.6017G>Cā(p.Ser2006Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,610 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).
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.6017G>C | p.Ser2006Thr | missense_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.5648G>C | p.Ser1883Thr | missense_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.6017G>C | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250602Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135658
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461610Hom.: 0 Cov.: 46 AF XY: 0.00000550 AC XY: 4AN XY: 727104
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
The p.S2006T variant (also known as c.6017G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 6017. The serine at codon 2006 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
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Breast and/or ovarian cancer Uncertain:1Benign:1
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not specified Uncertain:1
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not provided Uncertain:1
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 6245G>C; This variant is associated with the following publications: (PMID: 31131967, 28726806) -
Familial cancer of breast Uncertain:1
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Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 2006 of the BRCA2 protein (p.Ser2006Thr). This variant is present in population databases (rs144784912, gnomAD 0.006%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 35918668). ClinVar contains an entry for this variant (Variation ID: 188433). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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