rs276174803
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_ModeratePM2BP6
The NM_000059.4(BRCA2):c.10095delinsGAATTATATCT(p.Ser3366AsnfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V3365V) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.10095delinsGAATTATATCT | p.Ser3366AsnfsTer4 | frameshift_variant | 27/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.10095delinsGAATTATATCT | p.Ser3366AsnfsTer4 | frameshift_variant | 27/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:6
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Ser3366Asnfs*4 variant was identified in 19 of 9215 proband chromosomes (frequency: 0.002) from individuals or families with pancreatic and hereditary breast and ovarian cancer and identified in 1 of 490 chromosomes (frequency: 0.002) from healthy individuals (Borg 2010, Hahn 2003, Koczowska 2016, Wojcik 2016, Ratajska 2008, Balabas 2010, Houdayer 2012, Meindl 2002, Kim 2005, Thomassen 2008, Machakova 2008, Stegel 2011). The variant was identified in ClinVar (classified as benign by Ambry Genetics, BIC, Integrated Genetics, and 2 other submitters, uncertain significance by PreventionGenetics, Western University and 2 other submitters and likely benign by Invitae, Pathway Genomics and 1 other submitter), LOVD 3.0 (observed 1x), UMD-LSDB (observed 25x) .The variant was not identified in dbSNP, Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In UMD-LSDB, the variant was observed in samples with co-occurring pathogenic BRCA1 variants (c.2959A>T p.Lys987*, c.1171G>T p.Glu391*). Additionally, the variant had no observed effect on both BRCA2 mRNA expression and in vitro splicing (Stordal 2013, Houdayer 2012). The c.10095delinsGAATTATATCT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3366 and leads to a premature stop codon at position 3369. This alteration is then predicted to result in a truncated or absent protein. Truncations downstream of the Lys3326 residue are predicted to retain the biological functions of BRCA2 and are not believed to be pathogenic, however this has not been tested experimentally (Borg 2010, Negura 2012). 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. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 30113427, 22505045, 12569143) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 11, 2022 | PM2 - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 03, 2016 | Variant summary: The c. 10095delinsGAATTATATCT (p.Ser3366Asnfs) variant in BRCA2 has been reported in the literature to be found in prostate, breast and ovarian cancer patients, without strong evidence for causality. The variant was identified in at least 1 healthy individual from the literature, but not amongst the 1000G, ExAC or and ESP cohort. Multiple reputable clinical labs/databases have classified the variant as benign/likely benign. The variant is located 51 amino acids from the end of the protein and 40 amino acids downstream from the c.9976A>T (p.Lys3326X) variant, which was proven to be non pathogenic and It is generally accepted that truncations downstream of Lys3326 are non-pathogenic. Additionally, the variant was found to co-occur with several pathogenic BRCA1/2 variants via UMD: BRCA2 c.17_18delAA (p.Lys6Argfs), BRCA1 c.2959A>T (p.Lys987X), BRCA1 c.1171G>T (p.Glu391X). The variant was also shown to have no effect on splicing (Houdayer_2012). The variant of interest shows strong evidence for neutrality, and has been classified as a benign variant. - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 17, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | BRCA2: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 09, 2023 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:4
Likely benign, no assertion criteria provided | literature only | Pathway Genomics | Jul 24, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 17, 2010 | - - |
Likely benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | research | Dr. Peter K. Rogan Lab, Western University | Dec 22, 2015 | Sequenced patient with familial breast cancer - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 02, 2016 | Interpretation was last updated within 1 year from 2/2/2016 11:04 AM - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 06, 2020 | - - |
Benign, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Hereditary cancer-predisposing syndrome Benign:2
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 | Sep 22, 2015 | - - |
Breast carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Sep 11, 2021 | - - |
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 | Dec 05, 2022 | - - |
BRCA2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 11, 2023 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at