rs80358528
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):c.2716A>G(p.Thr906Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,457,270 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).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 missense
NM_000059.4 missense
Scores
1
15
Clinical Significance
Conservation
PhyloP100: 0.113
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 -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.112930536).
BP6
Variant 13-32337071-A-G is Benign according to our data. Variant chr13-32337071-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37798.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=2, Uncertain_significance=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.2716A>G | p.Thr906Ala | missense_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.2716A>G | p.Thr906Ala | missense_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000243 AC: 6AN: 246548Hom.: 0 AF XY: 0.0000225 AC XY: 3AN XY: 133176
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GnomAD4 exome AF: 0.0000185 AC: 27AN: 1457270Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14AN XY: 724560
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:3
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 22, 2012 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Thr906Ala variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, UMD, or LOVD databases. The variant was listed in dbSNP (ID: rs80358528) “With non-pathogenic allele”; however, no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The variant was identified in the BIC database 3X as a variant with unknown clinical importance, and was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Thr906 residue is not conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. - |
| Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 20, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 04, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 30, 2016 | - - |
not provided Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 23, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 03, 2023 | The frequency of this variant in the general population, 0.000045 (5/112094 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in 8 individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The variant has also been reported as somatic variant in an ovarian cancer tumor (PMID: 32483276 (2020)) as well as in an unaffected individual (PMID: 31837001 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 27, 2021 | Variant summary: BRCA2 c.2716A>G (p.Thr906Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250434 control chromosomes (gnomAD and Guo_2020). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2716A>G has been reported in the literature as a non-informative genotype in at-least one patient with Ovarian adenocarcinoma (Aref-Eshghi_2020). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported (BRCA1 c.3664G>T, p.Glu1222X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=1) or likely benign (n=4). Based on the lack of evidence supporting an actionable outcome as outlined above, the variant was classified as likely benign to reflect the prevailing peer consensus. - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 10, 2021 | - - |
BRCA2-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 14, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary breast ovarian cancer syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
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
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
N;N
REVEL
Benign
Sift
Benign
D;D
Sift4G
Benign
T;T
Vest4
MutPred
Loss of stability (P = 0.1547);Loss of stability (P = 0.1547);
MVP
MPC
0.022
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at