rs80358457
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_000059.4(BRCA2):c.1744A>C(p.Thr582Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,613,026 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. T582A) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.1744A>C | p.Thr582Pro | missense_variant | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1744A>C | p.Thr582Pro | missense_variant | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000232 AC: 58AN: 250240Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135360
GnomAD4 exome AF: 0.000103 AC: 150AN: 1460680Hom.: 1 Cov.: 35 AF XY: 0.000107 AC XY: 78AN XY: 726628
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6AN XY: 74502
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:4
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
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 = 0.0000224 - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 01, 2009 | - - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 03, 2024 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 23, 2019 | Variant summary: BRCA2 c.1744A>C (p.Thr582Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 250296 control chromosomes, predominantly at a frequency of 0.0032 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1744A>C has been reported in the literature in individuals affected with Breast and Ovarian Cancer. However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.505C>T, p.Gln169Ter), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Mondal_2012). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4x benign-including one expert panel, 3x likely benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign. - |
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 | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | BRCA2: BP1, BP4, BS3:Supporting - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2020 | This variant is associated with the following publications: (PMID: 17924331, 24323938, 21990134, 12624724, 9971877, 19491284, 15117986, 17301269, 26260725, 22771033, 15168169, 18779604, 27124784, 27383479, 26332594, 28782087, 29202657, 28111427, 30415210, 32426482) - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 11, 2023 | - - |
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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 08, 2015 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 10, 2021 | - - |
BRCA2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 15, 2022 | 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.Thr582Pro variant has been identified in 6 out of 1488 proband chromosomes (frequency 0.004) in Korean, Asian American, and North American individuals or families with breast and pancreatic cancers ( Couch 2007, Haffty 2009, Choi 2004, Kurian 2008). In a study elucidating the function of BRCA2 in whole chromosomal instability seen in BRCA2-deficient tumors, the variant disrupted interactions with associated partners involved in maintaining chromosomal stability but has no effect on BRCA2-dependent homologous recombination repair of DNA damage (Mondal 2012). The variant was identified in dbSNP (ID: rs80358457) “With uncertain significance, untested allele”, in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 27 of 120326 chromosomes (frequency: 0.0002) (or 27 individuals from a population of East Asians, and none from European (Non-Finnish), Other, African, Latino, South Asian, or European (Finnish) individuals); and was identified by our laboratory in 3 individuals with breast cancer. The variant was also identified in the Clinvitae database (2X, classifications benign and conflicting interpretations), Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database (classified as not pathogenic/of no clinical significance), the ClinVar database (reviewed by an expert panel and classified as benign; specifically, classified as benign by ENIGMA, Ambry Genetics and Sharing Clinical Reports Project (SCRP) (derived from Myriad reports), classified as uncertain significance by BIC, and unclassified by Invitae), GeneInsight COGR database (unclassified by a clinical laboratory), the BIC database (7X with unknown clinical importance, classification pending), and UMD (unavailable). The p.Thr582 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Other variants were also reported impacting the same site including c.1744A>G, p.Thr582Ala (BIC reported 3 times with unknown clinical significance) and c.1744A>T, p.Thr582Ser (Myriad reported as a polymorphism - personal communication). 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
Likely benign, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at