chr13-32363351-G-T
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBP6_Very_Strong
The NM_000059.4(BRCA2):c.8149G>T(p.Ala2717Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00139 in 1,614,110 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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. A2717V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8149G>T | p.Ala2717Ser | missense_variant | 18/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8149G>T | p.Ala2717Ser | missense_variant | 18/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00128 AC: 195AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00109 AC: 275AN: 251278Hom.: 0 AF XY: 0.00114 AC XY: 155AN XY: 135824
GnomAD4 exome AF: 0.00140 AC: 2053AN: 1461862Hom.: 2 Cov.: 31 AF XY: 0.00134 AC XY: 977AN XY: 727226
GnomAD4 genome ? AF: 0.00128 AC: 195AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81AN XY: 74450
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:14
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Aug 24, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Benign, reviewed by expert panel | curation | ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen | Apr 23, 2024 | The c.8149G>T variant in BRCA2 is a missense variant predicted to cause substitution of Alanine by Serine at amino acid 2717 (p.Ala2717Ser). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.001751 in the Latino/Admixed American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.0816, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. SpliceAI predictor score of 0.03 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). Reported by 3 calibrated studies to exhibit protein function similar to benign control variants (PMIDs: 29988080, 33609447, 32444794) (BS3 met). This variant has been observed in 2 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2.288E-117 (based on Cosegregation LR=4.52E-08; Pathology LR=5.249E-08; Family History LR=1.995E-19; Case-Control LR=4.83E-84), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: Internal lab contributors). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP4, BS3, BS2, BP5_Very strong). - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Pathway Genomics | Nov 06, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 16, 2015 | - - |
Benign, criteria provided, single submitter | literature only | Counsyl | Mar 05, 2014 | - - |
not specified Uncertain:1Benign:6Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 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: Clinvar: 10 labs classify as LB/Ben; ExAC: 0.2% (118/66734) European chromosomes - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
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 | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 26, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 22, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 15, 2014 | - - |
not provided Benign:6
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 07, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 18, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | BRCA2: BP1, BS3:Supporting, BS1 - |
Hereditary cancer-predisposing syndrome Benign:5
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Jan 05, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 11, 2015 | - - |
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 | Vantari Genetics | Dec 18, 2015 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 08, 2020 | - - |
Hereditary breast ovarian cancer syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 03, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Breast and/or ovarian cancer Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Feb 15, 2001 | - - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 17, 2023 | - - |
Fanconi anemia complementation group D1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 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. - |
BRCA2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 16, 2023 | 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 p.Ala2717Ser variant has been identified in five individuals from our laboratory, 36 times in the UMD-BRCA2 database and 112 times in the BIC database. The variant was identified in 19 of 7810 proband chromosomes in individuals with breast, ovarian and prostate cancer patients (Edwards 2003, Diez 2003, Lubinski 2004, Salazar 2006, Giannini 2006, Soegaard 2008, Caux-Moncoutier 2009, Capanu 2011). However, an inadequate number of control chromosomes were tested to establish the variants frequency in the general population. This variant is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897747) and was identified in more than one population with an average heterozygosity of 0.004+/-0.046, increasing the likelihood that this is a low frequency benign variant. The Ala2717 residue is not highly conserved in mammals and neither computational analyses (SIFT, AlignGVGD) nor other in silico protein modeling predictions (Karchin 2008, Spurdle 2008) suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Finally, this variant was identified in at least three individuals in the UMD database who had a second premature truncating variant that is expected to be pathogenic, increasing the likelihood that the p.Ala2712Ser variant is not clinically significant. In summary, based on the above information this variant is classified as Benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at