ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.10095delinsGAATTATATCT (p.Ser3366fs) (rs276174803)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122897 SCV000166155 likely benign Hereditary breast and ovarian cancer syndrome 2016-11-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129586 SCV000184369 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000112839 SCV000267835 benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000122897 SCV000324858 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-02-02 criteria provided, single submitter clinical testing Interpretation was last updated within 1 year from 2/2/2016 11:04 AM
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590484 SCV000694492 benign not provided 2016-05-03 criteria provided, single submitter clinical testing 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.
PreventionGenetics,PreventionGenetics RCV000590484 SCV000805640 uncertain significance not provided 2017-09-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590484 SCV000888968 benign not provided 2019-04-04 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769707 SCV000901126 uncertain significance Breast and/or ovarian cancer 2017-10-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129586 SCV001355389 likely benign Hereditary cancer-predisposing syndrome 2015-09-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286963 SCV001473596 likely benign none provided 2019-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000590484 SCV001939400 benign not provided 2015-03-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30113427, 22505045, 12569143)
Breast Cancer Information Core (BIC) (BRCA2) RCV000112839 SCV000145751 benign Breast-ovarian cancer, familial 2 2010-12-17 no assertion criteria provided clinical testing
Pathway Genomics RCV000112839 SCV000187735 likely benign Breast-ovarian cancer, familial 2 2014-07-24 no assertion criteria provided literature only
Dr. Peter K. Rogan Lab,Western University RCV000122897 SCV000262591 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-12-22 no assertion criteria provided research Sequenced patient with familial breast cancer
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496401 SCV000588019 benign not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000590484 SCV001552856 likely benign not provided no assertion criteria provided clinical testing 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.
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001647083 SCV001852743 likely pathogenic Breast carcinoma 2021-09-11 no assertion criteria provided clinical testing

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