ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9371A>T (p.Asn3124Ile) (rs28897759)

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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 RCV000130337 SCV000185187 pathogenic Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Other data supporting pathogenic classification,Significant disease association in appropriately sized case-control study(ies),Other strong data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Breast Cancer Information Core (BIC) (BRCA2) RCV000031816 SCV000147620 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000130337 SCV000684058 pathogenic Hereditary cancer-predisposing syndrome 2016-10-19 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031816 SCV000328117 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031816 SCV000677707 likely pathogenic Breast-ovarian cancer, familial 2 2016-06-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045802 SCV000592279 pathogenic Hereditary breast and ovarian cancer syndrome 2015-09-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000505786 SCV000228185 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000505786 SCV000278888 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9371A>T at the cDNA level, p.Asn3124Ile (N3124I) at the protein level, and results in the change of an Asparagine to an Isoleucine (AAC>ATC). Using alternate nomenclature, this variant has been previously published as BRCA2 9599A>T. This variant was observed in multiple individuals with a personal and/or family history of male and female breast and/or ovarian cancer, and was described as a recurrent pathogenic variant in the Polish population (Kwiatkowska 2001, Akbari 2011, Balabas 2011, Levanat 2012, Surowy 2014, Couch 2015, Kluska 2015, Wojcik 2016). Functional studies found strong evidence for pathogenicity based on impairment of the structure and stability of the OB3 interface, decreased homology-directed DNA break repair and inability to rescue the lethality of BRCA2-deficient mouse embryonic stem cells (Biswas 2012, Guidugli 2013, Surowy 2014). In addition, BRCA2 Asn3124Ile was strongly predicted by Lindor et al. (2012) to be likely pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants, while another multifactorial likelihood model predicted this variant to be pathogenic (Guidugli 2018). BRCA2 Asn3124Ile was not observed at a significant frequency in large population cohorts (Lek 2016). BRCA2 Asn3124Ile is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider BRCA2 Asn3124Ile to be pathogenic.
GeneKor MSA RCV000585706 SCV000693549 likely pathogenic Familial cancer of breast 2018-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000031816 SCV000593759 pathogenic Breast-ovarian cancer, familial 2 2016-02-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031816 SCV000743365 likely pathogenic Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045802 SCV000695235 pathogenic Hereditary breast and ovarian cancer syndrome 2017-08-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9371A>T (p.Asn3124Ile) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/127780 control chromosomes at a frequency of 0.0000157, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Numerous publications report the identification of this variant in patients with breast/ovarian/prostate cancer. The single largest study of families presenting with this variant reports the suggestive co-segregation (20 families tested; variant present in 7 unaffected family members and variant absent in 3 affected family members) and provides likelyhood ratio data that is suggestive, but not entirely conclusive, of pathogenicity (Biswas_2012). Functional studies show the variant to disrupts BRCA2 homology-directed DNA break repair activity, and that it is unable to rescue the phenotype in BRCA2 null (Guidugli_2012, Biswas_2012). Another study showed no accumulation of increased chromosomal damage in lymphocytes from a carrier after irradiation (Becker_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic, including two most recent submissions with pathogenic classification in 2016. Taken together, this variant is classified as pathogenic.
Invitae RCV000045802 SCV000073815 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 3124 of the BRCA2 protein (p.Asn3124Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is present in population databases (rs28897759, ExAC 0.003%). This variant has been reported in many individuals and families affected with breast and ovarian cancer (PMID: 11102977, 16284991, 18703817, 21120943, 21232165, 21965345, 22366370, 22729890, 25948282). It is also known as 9599A>T in the literature. ClinVar contains an entry for this variant (Variation ID: 38233). Epidemiological studies show that this variant is a common cause of breast and ovarian cancer in Poland and Germany, being identified in 1.45% (9 cases) and 0.47% (11 cases) of the cases, respectively, while it has not been found in a cohort of more than 3,000 individuals from those populations (PMID: 11802209, 20383589, 24728577, 25948282). In addition, based on multifactorial likelihood and history weighting algorithms using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 23108138, 25085752). Experimental studies have shown that this missense change disrupts BRCA2 homology-directed DNA break repair activity, and is unable to rescue the phenotype present in ES cells null for BRCA2 (PMID: 22678057, 23108138). However, another study showed that lymphocytes from a carrier did not accumulate an increased level of chromosomal damage after irradiation (PMID: 22729890). The relevance of this last study is uncertain. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000045802 SCV000838902 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505786 SCV000600859 pathogenic not provided 2017-05-08 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045802 SCV000588000 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031816 SCV000054424 pathogenic Breast-ovarian cancer, familial 2 2013-07-16 no assertion criteria provided clinical testing

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