chr13-32336452-G-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000059.4(BRCA2):c.2097G>T(p.Gln699His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,696 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q699R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 missense
NM_000059.4 missense
Scores
2
14
Clinical Significance
Conservation
PhyloP100: -0.149
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.15610453).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.2097G>T | p.Gln699His | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.2097G>T | p.Gln699His | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461696Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727148
GnomAD4 exome
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13
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1461696
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33
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7
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727148
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2015 | This variant is denoted BRCA2 c.2097G>T at the cDNA level, p.Gln699His (Q699H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAT). Using alternate nomenclature, this variant would be defined as BRCA2 2325G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln699His 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 Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln699His occurs at a position that is not conserved and is located in the region of Interaction with NPM1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Gln699His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 10, 2023 | The BRCA2 c.2097G>T; p.Gln699His variant (rs80358486), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 51243). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.198). Due to limited information, the clinical significance of this variant is uncertain at this time. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 13, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 15, 2017 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 08, 2023 | This missense variant replaces glutamine with histidine at codon 699 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 23, 2003 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 08, 2009 | - - |
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 | Color Diagnostics, LLC DBA Color Health | Oct 21, 2021 | This missense variant replaces glutamine with histidine at codon 699 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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 | Jul 30, 2023 | The p.Q699H variant (also known as c.2097G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 2097. The glutamine at codon 699 is replaced by histidine, an amino acid with highly 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. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2023 | Variant summary: BRCA2 c.2097G>T (p.Gln699His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250642 control chromosomes (gnomAD). 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.2097G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported in BIC database (BRCA1 c.3756_3759delGTCT, p.Ser1253fs), providing supporting evidence for a benign role. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 10, 2024 | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 699 of the BRCA2 protein (p.Gln699His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51243). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Benign
T;T
Sift4G
Uncertain
D;D
Vest4
MutPred
Loss of catalytic residue at Q699 (P = 0.0666);Loss of catalytic residue at Q699 (P = 0.0666);
MVP
MPC
0.053
ClinPred
T
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at