rs80358649
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000059.4(BRCA2):c.3999C>G(p.Asn1333Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N1333N) has been classified as Likely benign.
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.3999C>G | p.Asn1333Lys | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.3999C>G | p.Asn1333Lys | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000435 AC: 1AN: 229624Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 124348
GnomAD4 exome AF: 6.98e-7 AC: 1AN: 1433684Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 711268
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 02, 2023 | The c.3999C>G (p.N1333K) alteration is located in exon 11 (coding exon 10) of the BRCA2 gene. This alteration results from a C to G substitution at nucleotide position 3999, causing the asparagine (N) at amino acid position 1333 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 12, 2019 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Oct 29, 2003 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 07, 2008 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 24, 2022 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1333 of the BRCA2 protein (p.Asn1333Lys). This variant is present in population databases (rs80358649, gnomAD 0.004%). 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: 126030). 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