rs28897745
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_000059.4(BRCA2):c.7994A>G(p.Asp2665Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000403 in 1,613,748 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00040 ( 1 hom. )
Consequence
BRCA2
NM_000059.4 missense
NM_000059.4 missense
Scores
10
4
2
Clinical Significance
Conservation
PhyloP100: 7.08
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 Benign. Variant got -8 ACMG points.
BP6
Variant 13-32363196-A-G is Benign according to our data. Variant chr13-32363196-A-G is described in ClinVar as [Benign]. Clinvar id is 38134.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32363196-A-G is described in Lovd as [Benign]. Variant chr13-32363196-A-G is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7994A>G | p.Asp2665Gly | missense_variant | 18/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7994A>G | p.Asp2665Gly | missense_variant | 18/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.7625A>G | p.Asp2542Gly | missense_variant | 18/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*52A>G | non_coding_transcript_exon_variant | 17/26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259 | n.*52A>G | 3_prime_UTR_variant | 17/25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.000480 AC: 73AN: 152220Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000231 AC: 58AN: 250552Hom.: 1 AF XY: 0.000207 AC XY: 28AN XY: 135486
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GnomAD4 exome AF: 0.000396 AC: 578AN: 1461410Hom.: 1 Cov.: 31 AF XY: 0.000376 AC XY: 273AN XY: 727020
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GnomAD4 genome AF: 0.000479 AC: 73AN: 152338Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44AN XY: 74510
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ClinVar
Significance: Benign
Submissions summary: Uncertain:2Benign:18
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:5
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 18, 2019 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 2.60E-07 - |
Likely benign, criteria provided, single submitter | literature only | Counsyl | Dec 30, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not specified Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 20, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 7 reports in HGMD, 3 describe as neutral/nonpathogenic; ClinVar: 5 labs report as B/LB - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 26, 2017 | - - |
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 27, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2021 | This variant is associated with the following publications: (PMID: 17924331, 20104584, 27741520, 28050887, 28758972, 21120943, 18724707, 21952622, 21702907, 21520273, 22505045, 16489001, 19043619, 21990134, 23108138, 20215541, 12474142, 24916970, 28324225, 18559594, 16826315, 20127978, 16758124, 25682074, 24323938, 29394989, 31131967, 32772980, 32438681, 29884841) - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 29, 2016 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 28, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 2014 | This alteration is classified as 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 24, 2014 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Fanconi anemia complementation group D1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
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 | Jun 16, 2023 | - - |
BRCA2-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 18, 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). - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Asp2665Gly variant was identified in the literature in 6 out of 5644 proband chromosomes (frequency 0.001) from individuals with breast, ovarian and prostate cancers, and was identified in 1 out of 360 control chromosomes (frequency 0.003) (Borg 2010, Chenevix-Trench 2006, Edwards 2003, Evans 2008, Peixoto 2006, Soegaard 2008). The variant was also listed in the dbSNP database (ID#: rs28897745) “With Likely benign allele”, with frequencies of 0.0005 in the 1000 Genomes Project and 0.006 in the HAPMAP-TSI cohort; and was also identified in the Exome Variant Server Exome Sequencing Project with a frequency of 0.0007 in European American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was identified in the HGMD, LOVD, ClinVar, the BIC database (26X with no clinical importance), and UMD (8X as a neutral variant). In the ClinVar database, the variant was classified as benign by the Sharing Clinical Reports Project (derived from Myriad reports) and Ambry Genetics, and as likely benign by Invitae. In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.3847_3848delGT (p.Val1283LysfsX2)), increasing the likelihood that the p.Asp2665Gly variant does not have clinical significance. p.Asp2665 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asp2665Gly variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this is not very predictive of pathogenicity. One functional assay found the variant had similar levels of homology-directed repair to wild-type BRCA2 (Guidugli 2013), and analysis of a tumour showed loss of the variant, suggesting that it is neutral (Chenevix-Trench 2006 16489001). In addition, multifactorial probability-based models classify the variant as likely non-pathogenic or benign (Chenevix-Trench 2006, Guidugli 2013) and one protein likelihood ratio model predicts the variant to be neutral (Karchin 2008 19043619). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Pathogenic
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Vest4
MVP
MPC
0.18
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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