rs80358566
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):c.3218A>G(p.Gln1073Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000668 in 1,601,338 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1073H) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.3218A>G | p.Gln1073Arg | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.3218A>G | p.Gln1073Arg | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000659 AC: 16AN: 242708Hom.: 0 AF XY: 0.0000686 AC XY: 9AN XY: 131184
GnomAD4 exome AF: 0.0000656 AC: 95AN: 1449100Hom.: 0 Cov.: 32 AF XY: 0.0000667 AC XY: 48AN XY: 719358
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74386
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3Benign:1
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 18, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 19, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2018 | This alteration is classified as likely 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 | Feb 22, 2016 | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 13, 2023 | Variant summary: BRCA2 c.3218A>G (p.Gln1073Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-05 in 242708 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.3218A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer, prostate cancer, urothelial cancer and uterine cancer (Zhu_2020, Alsop_2012, Lu_2012, Maier_2014, Rodriguez-Vida_2014, Lu_2015), without strong evidence for causality. In addition, this variant has been reported insignificantly present in both case and control cohorts in a large case-control study of breast cancer (4/60466 cases vs 3/53461 controls, Dorling_2021). Functional studies show that this variant alters the BRCA2-APRIN interaction independently of the BRC1-RAD51 interaction but was able to partially rescue homologous recombination in BRCA2-deficient cells to about 65% of normal function (Brough_2012). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=3, Likely benign, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 04, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2019 | This variant is associated with the following publications: (PMID: 28726806, 27067391, 26497743, 22293751, 22711857, 25111659) - |
Hereditary breast ovarian cancer syndrome Benign:2
Likely benign, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Jan 08, 2024 | . According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose this criterium: BP1 (strong benign): BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (spliceAI: BRCA2: 0.0) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 25, 2023 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Gln1073Arg variant was identified in dbSNP (ID: rs80358566) as “other”, Clinvitae database (classified as likely benign by ClinVar; uncertain significance by ClinVar and Invitae), the ClinVar database (classified as likely benign by SCRP, GeneDx; uncertain significance by Invitae, Ambry Genetics, BIC), the BIC database (3x with unknown clinical importance). This variant was also identified in the Exome Aggregation Consortium database (August 8th 2016) in 6 of 119496 chromosomes (freq. 0.00005) in the European population in 6 of 65970 chromosomes (freq.0.0001), but was not seen in African, Asian, Finnish, Latino and Other populations. The variant was not identified in the Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database, COSMIC and GeneInsight-COGR databases. The p.Gln1073 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the loss of a cryptic 3’ splice site. However, this information is not predictive enough to assume pathogenicity. In addition, the variant was identified, in a sample used as a positive control, as co-occurring with a pathogenic variant in BRCA1 (c.5136G>A, p.Trp1712X), increasing the likelihood this variant does not have clinical significance (Mucaki 2016). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at