rs80358387
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_000059.4(BRCA2):c.10045A>G(p.Thr3349Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000601 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T3349N) has been classified as Uncertain significance.
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.10045A>G | p.Thr3349Ala | missense_variant | 27/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.10045A>G | p.Thr3349Ala | missense_variant | 27/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000112 AC: 28AN: 251090Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135728
GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41AN XY: 727210
GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74360
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:4
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 08, 2008 | - - |
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 = 0.0000000919 - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Benign:5
Likely benign, 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: ExAC: 5/11516 Latino; ClinVar: 4 B/LB, 1 VUS - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 28, 2020 | Variant summary: BRCA2 c.10045A>G (p.Thr3349Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251290 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00012 vs 0.00075), allowing no conclusion about variant significance. c.10045A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence of causality. One patient with the variant showed retention of the wild-type allele and loss of the allele harbouring the variant, suggesting the variant is not deleterious (Osorio_2002). Multifactorial models that incorporate family history, co-segregation, co-occurrence, and tumor pathology has predicted the variant to be likely neutral (Easton_2007, Lindor_2012). Multiple publications report experimental evidence evaluating an impact on protein function: splicing is not affected (Houdayer_2012) and HDR and cell survival assays show no difference from WT controls (Mesman_2018), altogether suggesting the variant has no effect on protein function. Seven clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign (n=3)/likely benign (n=5). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:4
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 | Vantari Genetics | Feb 04, 2016 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 08, 2015 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 05, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2019 | This variant is associated with the following publications: (PMID: 25637381, 21120943, 26420498, 10755399, 18403564, 22505045, 24323938, 21520273, 20104584, 12955716, 11979449, 25682074, 25348012, 17924331, 21990134, 29988080, 32123317) - |
Breast neoplasm Benign:1
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
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