rs876659600
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000059.4(BRCA2):āc.2719A>Gā(p.Lys907Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K907N) 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.2719A>G | p.Lys907Glu | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.2719A>G | p.Lys907Glu | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458100Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 725054
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign: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 | Nov 18, 2022 | The p.K907E variant (also known as c.2719A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2719. The lysine at codon 907 is replaced by glutamic acid, an amino acid with similar properties. This alteration was not observed in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 30, 2024 | Variant summary: BRCA2 c.2719A>G (p.Lys907Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-06 in 345874 control chromosomes, including case-control studies (gnomAD, Guo_2020, Okawa_2023, Momozawa_2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2719A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31837001, 30287823, 36243179). ClinVar contains an entry for this variant (Variation ID: 232177). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast cancer, susceptibility to Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital | Mar 25, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 13, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2947A>G; This variant is associated with the following publications: (PMID: 25348012, 31853058, 30287823, 31131967, 29884841, 32377563, 32467295) - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 08, 2022 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 907 of the BRCA2 protein (p.Lys907Glu). 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: 232177). 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