chr13-32356532-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000059.4(BRCA2):c.7540A>G(p.Lys2514Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2514N) has been classified 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7540A>G | p.Lys2514Glu | missense_variant | 15/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7540A>G | p.Lys2514Glu | missense_variant | 15/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727246
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74386
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 19, 2023 | This missense variant replaces lysine with glutamic acid at codon 2514 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer and an individual affected with gastric cancer (PMID: 27273131, 36627197, 37060015), but also in a general population study in the literature (PMID: 33428613). This variant has not been identified 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. - |
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 19, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2023 | Published functional studies suggest no splice defect and no effect on RNA (Byers et al., 2016); Observed in an individual with breast cancer, but also in a general population study (Byers et al., 2016; Tokunaga et al., 2021); 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 7768A>G; This variant is associated with the following publications: (PMID: 29884841, 32377563, 33428613, 12228710, 27273131) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 28, 2023 | This missense variant replaces lysine with glutamic acid at codon 2514 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer and an individual affected with gastric cancer (PMID: 27273131, 36627197, 37060015), but also in a general population study in the literature (PMID: 33428613). This variant has not been identified 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 05, 2022 | The p.K2514E variant (also known as c.7540A>G), located in coding exon 14 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7540. The lysine at codon 2514 is replaced by glutamic acid, an amino acid with similar properties. In one study, this alteration was detected in a female patient with breast cancer at age 37, and RNA analysis showed that this alteration did not cause abnormal splicing (Byers H et al. Eur. J. Hum. Genet., 2016 11;24:1591-1597).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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 | Oct 11, 2019 | Variant summary: BRCA2 c.7540A>G (p.Lys2514Glu) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251316 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7540A>G has been reported in the literature in an individual affected with Hereditary Breast Cancer (Byers_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 20, 2023 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2514 of the BRCA2 protein (p.Lys2514Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 27273131). ClinVar contains an entry for this variant (Variation ID: 220661). 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