chr13-32398243-G-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000059.4(BRCA2):c.9730G>A(p.Val3244Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,614,000 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3244F) has been classified as Benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9730G>A | p.Val3244Ile | missense_variant | 27/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.9361G>A | p.Val3121Ile | missense_variant | 27/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*1788G>A | non_coding_transcript_exon_variant | 26/26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259.2 | n.*1788G>A | 3_prime_UTR_variant | 26/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00721 AC: 1097AN: 152140Hom.: 16 Cov.: 32
GnomAD3 exomes AF: 0.00180 AC: 453AN: 251200Hom.: 5 AF XY: 0.00133 AC XY: 180AN XY: 135790
GnomAD4 exome AF: 0.000724 AC: 1058AN: 1461742Hom.: 8 Cov.: 31 AF XY: 0.000638 AC XY: 464AN XY: 727174
GnomAD4 genome AF: 0.00720 AC: 1096AN: 152258Hom.: 16 Cov.: 32 AF XY: 0.00704 AC XY: 524AN XY: 74440
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:7
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jan 12, 2015 | Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.02642 (African), derived from 1000 genomes (2012-04-30). - |
Benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Oct 03, 2023 | BA1 based on allele frequency in AFR of 0.0249 in gnomAD. - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | literature only | Counsyl | Mar 18, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
not specified Benign:7Other:1
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 13, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 29, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Hereditary breast ovarian cancer syndrome Benign:5
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Benign, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 14, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Apr 14, 2015 | - - |
not provided Benign:4
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | BRCA2: BP4, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 24, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 23, 2017 | - - |
Hereditary cancer-predisposing syndrome Benign:4
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 05, 2015 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 25, 2020 | - - |
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 | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jan 16, 2018 | - - |
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 13, 2022 | - - |
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 10, 2015 | - - |
BRCA2-related cancer predisposition Benign:1
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | - - |
Fanconi anemia complementation group D1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
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.Val3244Ile variant was identified in the literature in 5/7922 proband chromosomes (frequency: 0.001) from individuals with breast cancer; however, no control chromosomes were tested to establish the frequency of the variant in the general population (Borg 2010, Caux-Moncoutier 2011; Haffty 2009). The variant was also identified in the BIC database (73X with unknown clinical importance) and in UMD (28X as an unclassified variant) where it was listed to co-occur with a pathogenic mutation in BRCA1 (c.2551G>T (p.Glu851X)), increasing the likelihood that this variant may not have clinical importance. The p.Val3244 residue is not conserved in mammals, and the variant amino acid Isoleucine (Ile) is present in macaque at this position, increasing the likelihood that an alteration to this residue may not have functional significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not predict any effect on the protein function; however, this information is not predictive enough to rule out pathogenicity. The variant is listed in dbSNP as coming from a "clinical source" (ID#: rs11571831) with a minor allele frequency of 0.006 (1000 Genomes). It was also identified in the NHLBI Exome Sequencing Project with a frequency of 0.025 in African American alleles, and in several HapMap populations including HapMap-YRI (frequency: 0.032), HapMap-JPT (frequency: 0.03) and HapMap-CEU (frequency: 0.033), increasing the likelihood that this is a low frequency benign polymorphism in certain populations of origin. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at