ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9672dup (p.Tyr3225fs) (rs80359773)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130631 SCV000185507 pathogenic Hereditary cancer-predisposing syndrome 2017-03-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA2) RCV000114151 SCV000147696 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000130631 SCV000911347 pathogenic Hereditary cancer-predisposing syndrome 2015-10-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000114151 SCV000328160 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000114151 SCV000744792 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000197712 SCV000592302 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-24 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000114151 SCV000733341 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000114151 SCV000301407 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000372727 SCV000329588 pathogenic not provided 2018-09-20 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.9672dupA at the cDNA level and p.Tyr3225IlefsX30 (Y3225IfsX30) at the protein level. The normal sequence, with the base that is duplicated in brackets, is AGAT[dupA]TATT. The duplication causes a frameshift, which changes a Tyrosine to an Isoleucine at codon 3225, and creates a premature stop codon at position 30 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. BRCA2 c.9672dupA, previously published as BRCA2 9900insA, has been observed in the heterozygous state in multiple suspected hereditary breast/ovarian cancer families, and in the compound heterozygous or homozygous state in at least three individuals with Fanconi anemia (Howlett 2002, van der Hout 2006, Tea 2014, Dodgshun 2016, Rump 2016). Based on currently available information, we consider this variant to be pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000114151 SCV000743528 pathogenic Breast-ovarian cancer, familial 2 2014-10-10 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000130631 SCV000803165 pathogenic Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000197712 SCV000695261 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-26 criteria provided, single submitter clinical testing Variant summary: The c.9672dupA variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a known disease mechanism for BRCA2-related phenotypes. Truncations downstream of this position have been classified as pathogenic/likely pathogenic by our laboratory (e.g. c.9788delA, c.9800dupA, p.Tyr3308X, etc.). This variant is not found in 120572 control chromosomes including the large and broad populations of ExAC. It was reported in multiple patients affected with breast and/or ovarian cancer reported in clinical database/publications. In addition, the variant is reported to cause Fanconi Anemia in compound heterozygous with other pathogenic/likely pathogenic variants. This variant was also found in homozygous state in one patient with intellectual disability and microcephaly who had focal temporal cortical dysplasia. Multiple clinical laboratories as well as reputable databases have classified it as pathogenic. Taken together, this variant has been classified as Pathogenic.
Invitae RCV000197712 SCV000255257 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 27 of the BRCA2 mRNA (c.9672dupA), causing a frameshift at codon 3225. This creates a premature translational stop signal in the last exon of the BRCA2 mRNA (p.Tyr3225Ilefs*30). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 195 amino acids of the BRCA2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected by breast and/or ovarian cancer (PMID: 24156927, 16683254). It has been reported in trans with a pathogenic variant in BRCA2 in an individual with Fanconi anemia (PMID: 12065746). This variant is also known as 9900insA in the literature. ClinVar contains an entry for this variant (Variation ID: 126217). Experimental evidence indicates that this variant encodes a truncated protein product (PMID: 12065746), and that cells carrying this variant display increased sensitivity to mitomycin C (PMID: 12065746). This variant removes a stretch of 36 conserved residues (amino acids 3270-3305) in BRCA2 that is important for interaction with RAD51 to mediate homologous recombination during the repair of double-strand DNA breaks (PMID: 17515903). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000197712 SCV000605805 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-28 criteria provided, single submitter clinical testing The p.Tyr3225fs variant in BRCA2 has been reported in the heterozygous state in >30 individuals with BRCA2-associated cancers and in the compound heterozygous s tate in 1 individual with Fanconi anemia (Howlett 2002, Tea 2014, Hout 2006, Dru sedau 2013, Karami 2013, Breast Cancer Information Core (BIC) database). This va riant was absent from large population studies. This variant is predicted to cau se a frameshift, which alters the protein?s amino acid sequence beginning at pos ition 3225 and leads to a premature termination codon 30 amino acids downstream. Heterozygous loss of function of the BRCA2 gene is an established disease mecha nism in hereditary breast and ovarian cancer (HBOC). In summary, this variant me ets criteria to be classified as pathogenic for HBOC in an autosomal dominant ma nner.
Michigan Medical Genetics Laboratories,University of Michigan RCV000114151 SCV000196029 pathogenic Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
OMIM RCV000009922 SCV000030143 pathogenic Fanconi anemia, complementation group D1 2002-07-26 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000372727 SCV000889186 pathogenic not provided 2018-03-02 criteria provided, single submitter clinical testing

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