13-32338925-T-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PP3_ModerateBP6_Very_Strong
The NM_000059.4(BRCA2):c.4570T>G(p.Phe1524Val) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. F1524C) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.4570T>G | p.Phe1524Val | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.4570T>G | p.Phe1524Val | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152140Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250548Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135636
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461644Hom.: 0 Cov.: 46 AF XY: 0.0000234 AC XY: 17AN XY: 727116
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74326
ClinVar
Submissions by phenotype
not specified Benign:6
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 14, 2017 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 25, 2019 | Variant summary: BRCA2 c.4570T>G (p.Phe1524Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250548 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4570T>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Caux-Moncoutier 2009, Haffty 2009, Meyer 2003, Meyer 2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A review of a multifactorial probability based model (Lindor 2012) that included a statistical weighting of segregation analysis, co-occurrence in trans, pathological profiles, personal and family history of cancer showed that, for this variant, odds in favor of causality was 1.02x10-3 and posterior probability of being deleterious was 2.08x10-5. Authors classify the variant as IARC Class 1 (Least Likely to be pathogenic) variant. Five ClinVar submissions including an expert panel (evaluation after 2014) cite the variant twice as benign and three times as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:4
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | 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 = 0.0000208 - |
Benign, criteria provided, single submitter | clinical testing | Counsyl | Mar 17, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Hereditary cancer-predisposing syndrome Benign:3
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 | curation | Sema4, Sema4 | Aug 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 28, 2015 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | BRCA2: BP1, BS3:Supporting - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Feb 07, 2003 | - - |
BRCA2-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 11, 2022 | This variant is classified as 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
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at