rs56070345
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBP6_Very_Strong
The NM_000059.4(BRCA2):c.7505G>A(p.Arg2502His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,614,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 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. R2502C) 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 -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7505G>A | p.Arg2502His | missense_variant | 15/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7505G>A | p.Arg2502His | missense_variant | 15/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152210Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251414Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135876
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461846Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 727228
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152328Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
Uncertain significance, 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 | PreventionGenetics, part of Exact Sciences | Oct 19, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | BRCA2: BP4, BS3:Supporting, BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 16, 2018 | The BRCA2 c.7505G>A; p.Arg2502His variant (rs56070345) is reported in patients with breast and ovarian cancer (Akbari 2011, Gayther 1999, Spearman 2008), but also in an unaffected individual (Balabanski 2014). This variant is reported in ClinVar (Variation ID: 52345) and found in the general population with an overall allele frequency of 0.007% (17/246182 alleles) in the Genome Aggregation Database. The arginine at codon 2502 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, this variant has been previously identified by our laboratory in a patient who also carries a pathogenic truncating BRCA1 variant. Based on available information, this variant is considered to be likely benign. REFERENCES Akbari MR et al. Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes. J Med Genet. 2011 Nov;48(11):783-6. Balabanski L et al. Next-generation sequencing of BRCA1 and BRCA2 in breast cancer patients and control subjects. Mol Clin Oncol. 2014 May;2(3):435-439. Gayther SA et al. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am J Hum Genet. 1999 Oct;65(4):1021-9. Spearman AD et al. Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol. 2008 Nov 20;26(33):5393-400. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2021 | This variant is associated with the following publications: (PMID: 10486320, 24504028, 19043619, 24772314, 21702907, 25583476, 18824701, 10882858, 25415331, 22505045, 28222693, 27616075, 28263838, 30696104) - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 09, 2018 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 15, 2017 | - - |
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 = 0.00054 - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 28, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 29, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 22, 2017 | 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. - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 08, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 03, 2022 | Variant summary: BRCA2 c.7505G>A (p.Arg2502His) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.1e-05 in 252472 control chromosomes, predominantly at a frequency of 0.00029 within the South Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7505G>A has been reported in the literature in individuals affected with breast- or ovarian cancer (e.g. Akbari_2011, Gayther_1999, Spearman_2008, Bolognesi_2014, Cunningham_2014, Davies_2018, Kraus_2016, Momozawa_2018), but also in controls (Bolognesi_2014, Balabanski_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been observed at our laboratory and in prominent databases (UMD-BRCA1 c.5096G>A, p.Arg1699Gln; Our laboratory-BRCA1 c.68_69delAG; ARUP laboratories-BRCA1, pathogenic variant is not specified), providing supporting evidence for a benign role. Two publications reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect on splicing (Houdayer_2012), and no effect on the BRCA2/DSS1 interaction (Caleca_2019). Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with a predominant consensus as benign/likely benign (n=11) (VUS, n=2). Based on the evidence outlined above, the variant was classified as benign. - |
Hereditary breast ovarian cancer syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at