rs56403624
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_000059.4(BRCA2):c.1385A>G(p.Glu462Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,611,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. E462D) 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.1385A>G | p.Glu462Gly | missense_variant | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1385A>G | p.Glu462Gly | missense_variant | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152256Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000246 AC: 61AN: 248384Hom.: 0 AF XY: 0.000275 AC XY: 37AN XY: 134302
GnomAD4 exome AF: 0.000252 AC: 368AN: 1459548Hom.: 0 Cov.: 35 AF XY: 0.000251 AC XY: 182AN XY: 725902
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74390
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:8
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 13, 2014 | - - |
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: Multiple publications classify as VUS/not pathogenic; ExAC: 27/66408 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+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Glu462Gly variant was identified in 16 of 5462 proband chromosomes (frequency: 0.003) from individuals with breast or ovarian cancer and was absent in 200 control chromosomes from theses studies (Capanu 2011, Farrugia 2008, Hadjisavvas 2003, Hadjisavvas 2004, Simard 2007, van Harssel 2010); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also reported in HGMD, LOVD, UMD (14X as a neutral variant), and the BIC database (37X with unknown clinical importance). This variant was identified in dbSNP (ID: rs56403624) “With non-pathogenic allele”, and at a low frequency (0.0003) in the NHLBI Exome Sequencing Project. This residue is conserved in mammals but not in lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional assays assessing cell survival, homologous recombination, centrosome regulation and nuclear localization have found no effect of the variant on normal BRCA2 function (Farrugia 2008, Wu 2005). In addition, five in silico studies predict this variant to be neutral or of little clinical significance (Capanu 2011 21520273, Easton 2007, Farrugia 2008, Lindor 2012, van Harssel 2010). This variant was not found to co-segregate with disease in an assessment of four families (Mohammadi 2009), and Simard (2007) found this variant co-occurring with a known deleterious mutation, increasing the likelihood that this variant does not have functional importance. Furthermore, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 16, 2021 | DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.1385A>G, in exon 10 that results in an amino acid change, p.Glu462Gly. This sequence change has been described in the gnomAD database with a frequency of 0.043% in the European sub-population (dbSNP rs56403624). The p.Glu462Gly change was reported to co-occur with a pathogenic sequence change in the BRCA2 gene (PMID: 16905680). In addition, this variant was found not to segregate with disease in affected families (PMID: 19200354). The p. Glu462Gly change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu462Gly change. Functional studies reported that this sequence change demonstrates similar protein function to the wild-type allele in assays of cellular survival and viability, homologous recombination repair and genome stability (PMID: 15695382). These collective evidences indicate that this is a likely benign sequence change. - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:7
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Sep 07, 2006 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 09, 2014 | - - |
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 = 0.00000293 - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
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 | BRCAlab, Lund University | Mar 02, 2020 | - - |
Likely benign, criteria provided, single submitter | literature only | Counsyl | Jul 10, 2014 | - - |
Hereditary cancer-predisposing syndrome Benign:4
Benign, criteria provided, single submitter | clinical testing | Vantari Genetics | Jan 06, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 05, 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 17, 2020 | - - |
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2021 | This variant is associated with the following publications: (PMID: 10717622, 24504028, 15026808, 21952622, 21520273, 24323938, 19200354, 15172753, 20104584, 19491284, 18451181, 21990134, 17924331, 15695382, 19563646, 16905680, 27616075, 29036293, 32444794) - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 14, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | BRCA2: BP1, BP4, BS3:Supporting, BS4 - |
Hereditary breast ovarian cancer syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 20, 2015 | Variant Summary: The c.1385A>G variant involves the alteration of a non-conserved nucleotide and 2/5 in silico tools predict a benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.023%, primarily observed in the European (Non-Finnish) cohort at a frequency of 0.041%. These frequencies do not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant was reported in the literature and databases in individuals who also have pathogenic BRCA1 (n=1) and BRCA2 (n=3) mutations (UMD, BIC, Simard_2007) suggesting a benign nature of the variant. Additionally, the variant was found to not segregate with disease in families tested (3 affected family members did not carry the variant; Gomez Garcia_2009). Functional studies showed the variant performed similarly to wild-type BRCA2 in assays of cellular survival and viability, homologous recombination repair, and genome instability (Wu_2005). Multiple reputable databases and clinical labs all classify the variant as benign/likely benign (Emory Genteics, UMD, ARUP, Ambry Genetics, SCRP, GeneDx, Counsyl) along with publications using multifactorial probability based models (Lindor_2012, Gomez Garcia_2009). All data, including co-segregation, functional assays, co-occurrence and the occurrence of this variant in the control population all support the classification of benign, therefore this variant has been classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at