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
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.
Ambry Genetics RCV000130631 SCV000185507 pathogenic Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing The c.9672dupA pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a duplication of A at nucleotide position 9672, causing a translational frameshift with a predicted alternate stop codon (p.Y3225Ifs*30). This mutation has been reported in multiple individuals and families with breast and/or ovarian cancer (van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66​; Reitsma W et al. Eur. J. Cancer 2013 Jan;49(1):132-41; Tea MK et al. Maturitas 2014 Jan;77(1):68-72). Further, this mutation was reported in trans with a likely pathogenic BRCA2 missense variant in a patient diagnosed with Fanconi anemia at 2 months of age, who later died of metastatic glioblastoma multiforme at age 4 <span style="font-family:sans-serif,arial,verdana,trebuchet ms">(Dodgshun AJ et al.<span style="font-family:sans-serif,arial,verdana,trebuchet ms"> Cancer Genet. 209(1-2):53-6)<span style="font-family:sans-serif,arial,verdana,trebuchet ms">. This mutation has also been detected in conjunction with another BRCA2 mutation in cells derived from a patient with Fanconi anemia (Howlett NG et al. Science 2002 Jul;297(5581):606-9; Feng Z et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Jan;108(2):686-91). Of note, this alteration is also designated as 9900insA in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Michigan Medical Genetics Laboratories,University of Michigan RCV000114151 SCV000196029 pathogenic Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
Invitae RCV000197712 SCV000255257 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-20 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) and an individual with medulloblastoma (PMID:29753700). 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.
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
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.
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.
Integrated Genetics/Laboratory Corporation of America RCV000197712 SCV000695261 pathogenic Hereditary breast and ovarian cancer syndrome 2021-02-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9672dupA (p.Tyr3225IlefsX30) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249832 control chromosomes (gnomAD and publication). c.9672dupA has been reported in the literature in multiple individuals affected with breast cancer and/or ovarian cancer (Couch_2015, Rebbeck_2018, BIC database). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic (n=10) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as 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
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
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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000372727 SCV000889186 pathogenic not provided 2018-03-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130631 SCV000911347 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-17 criteria provided, single submitter clinical testing
OMIM RCV000009922 SCV000030143 pathogenic Fanconi anemia, complementation group D1 2002-07-26 no assertion criteria provided literature only
Breast Cancer Information Core (BIC) (BRCA2) RCV000114151 SCV000147696 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353641 SCV000592302 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Tyr3225IlefsX30 variant was identified in individuals with hereditary breast and ovarian cancer (Karami 2013, Vos 2014) in the Netherlands populations and in Fanconi Anemia patients (Barber 2005, Howlett 2002, Lee 2014, Offit 2003, Reid 2005¬, Wang 2004), although no frequency data was given. The variant was also identified in dbSNP (ID: rs80359773) as “With Pathogenic allele”, Clinvitae database (pathogenic, Invitae), ARUP Laboratories BRCA Mutations Database (as definitely pathogenic), the ClinVar database (pathogenic, by multiple submitters), GeneInsight COGR database (unclassified) the BIC database (4x with unknown clinical importance), and UMD (3x with a “causal” classification). The c.9672dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3225 and leads to a premature stop codon at position 3254. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000114151 SCV000733341 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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