ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9371A>T (p.Asn3124Ile) (rs28897759)

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Total submissions: 26
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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) RCV000031816 SCV001161567 pathogenic Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Invitae RCV000045802 SCV000073815 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-27 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.
Ambry Genetics RCV000130337 SCV000185187 pathogenic Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing The p.N3124I pathogenic mutation (also known as c.9371A>T), located in coding exon 24 of the BRCA2 gene, results from an A to T substitution at nucleotide position 9371. The asparagine at codon 3124 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration has been classified as likely pathogenic (p>0.97) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton D et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee M et al. Hum. Mutat. 2012 Jan;33:22-8). This alteration is predicted to be pathogenic based on various computational approaches (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16; Rajasekaran R et al. Sheng Wu Gong Cheng Xue Bao. 2008 May;24:851-6; Levanat S et al. Gene. 2012 May;498:169-76). Additionally, this alteration has been predicted to be pathogenic based on cell-based functional assays (Biswas K et al. Hum. Mol. Genet. 2012 Sep;21:3993-4006; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75). This alteration has been described in several high risk breast and ovarian cancer families and in cohorts of individuals with ovarian cancer (Grzybowska E et al. Hum. Mutat. 2000 Dec;16:482-90; Kwiatkowska E et al. Hum. Mutat. 2001;17:73; Pal T et al. Cancer. 2005 Dec;104:2807-16; Balabas A et al. Fam. Cancer. 2010 Sep;9:267-74; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Akbari MR et al. J. Med. Genet. 2011 Nov;48:783-6; Surowy HM et al. Breast Cancer Res. Treat. 2014 Jun;145:451-60; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Kluska A et al. BMC Med Genomics 2015 May;8:19; Wojcik P et al. Hered. Cancer Clin. Pract. 2016 Feb;14:5; Thompson ER et al. J. Clin. Oncol. 2016 May;34:1455-9; Meisel C et al. Arch Gynecol Obstet. 2017 May;295(5):1227-1238). Of note, this alteration is also designated as 9599A>T in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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.
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
Genetic Services Laboratory, University of Chicago RCV000031816 SCV000593759 pathogenic Breast-ovarian cancer, familial 2 2016-02-01 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
Counsyl RCV000031816 SCV000677707 likely pathogenic Breast-ovarian cancer, familial 2 2016-06-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130337 SCV000684058 pathogenic Hereditary cancer-predisposing syndrome 2016-10-19 criteria provided, single submitter clinical testing
GeneKor MSA RCV000585706 SCV000693549 likely pathogenic Familial cancer of breast 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces Asparagine with Isoleucine at codon 3124 of the BRCA2 protein. The asparagine residue is highly conserved and is located in the oligonucleotide/oligosaccharide-binding, domain of the protein. There is a large physiochemical difference between asparagine and isoleucine (Grantham Score 149). This variant, also known as 9599A>T using an alternate transcript, has been reported in multiple individuals and families affected by breast and ovarian cancer (PMID: 11102977, 16284991, 18703817, 21120943, 21232165, 21965345, 22366370, 22729890, 25948282) and has been shown in epidemiological studies to be a common cause of breast and ovarian cancer in Poland and Germany (PMID: 11802209, 20383589, 24728577, 25948282). This variant is present in population databases at a low frequency (rs28897759, ExAC 0.003%). The mutation database ClinVar contains multiple entries for this variant (Variation ID: 38233).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045802 SCV000695235 pathogenic Hereditary breast and ovarian cancer syndrome 2021-03-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9371A>T (p.Asn3124Ile) results in a non-conservative amino acid change located in the BRCA2, OB3 domain (IPR015188) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-06 in 257878 control chromosomes (gnomAD and publication data). c.9371A>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Biswas_2012, Surowy_2014, Rebbeck_2018). Additionally, 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). These data indicate that the variant is very likely to be associated with disease. One co-occurrence with another pathogenic variant has been reported (BRCA1 c.5209A>T, p.Arg1737Ter, BIC database). 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, Ikegami_2020). Another study showed no accumulation of increased chromosomal damage in lymphocytes from a carrier after irradiation (Becker_2012). 20 ClinVar submitters (evaluation after 2014) cite the variant pathogenic (n=12) and likely pathogenic (n=8) , including one expert panel (ENIGMA) classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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
Mendelics RCV000045802 SCV000838902 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000031816 SCV001139258 likely pathogenic Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000031816 SCV001429468 likely pathogenic Breast-ovarian cancer, familial 2 2018-06-18 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000505786 SCV001446546 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000505786 SCV001450101 pathogenic not provided 2014-07-07 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000045802 SCV001478280 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-10 criteria provided, single submitter curation Data used in classification: This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (22.4) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant is classified on ClinVar as pathogenic by multiple USA accredited diagnostic laboratories (PP5_sup). Data not used in classification: The frequency of this variant is 2/123,053 individuals (gnomAD). There are additional reports of this variant in UMD (6), BIC (17), and BRCA2 LOVD (1).
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310163 SCV001499757 likely pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000505786 SCV001502177 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031816 SCV000054424 pathogenic Breast-ovarian cancer, familial 2 2013-07-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031816 SCV000147620 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353921 SCV000592279 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The p.Asn3124Ile variant was identified in 10 of 5262 proband chromosomes (frequency: 0.002) from individuals or families with hereditary breast and/or ovarian cancer (HBOC), and was not identified in 1500 control chromosomes from healthy individuals (Akbari 2011, Balabas 2010, Biswas 2012, Grzybowska 2000, Guidugli 2013, Karchin 2008, Levanat 2012, Meindl 2002, Rajasekaran 2008, Stegel 2011). The variant was identified in dbSNP as “with pathogenic allele” (ID: rs28897759), in Exome Aggregation Consortium (ExAC) database in 2 of 66670 alleles in the European (non-Finnish) population. It was also found in HGMD, LOVD, the ClinVar database (classified as Pathogenic variant by the Sharing Clinical Reports Project; classified as pathogenic by ambry Genetics; classified as Uncertain significance by BIC and classification not provided by Invitae). In GeneInsight through the COGR (http://opengenetics.ca/) the variant was identified 1x classified as “unknown” by a clinical laboratory, in the BIC database classified as 17x with unknown clinical importance, and in UMD 6x as an unknown variant. The p.Asn3124 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asn3124Ile may impact the protein. In one study (Biswas 2012), which examined co-segregation likelihood ratios, the data was suggestive, but not conclusive, of causality or pathogenicity (LR variant = 36.95) for the p.Asn3124Ile. In addition, in vitro functional studies showed the p.Asn3124Ile variant compromised BRCA2 function (Biswas 2012, Guidugli 2013). In silico structural studies predict the missense change to disrupt the structural integrity of the protein (Biswas 2012, Levanat 2012), and multifactorial likelihood-ratio models showed higher odds in favor of causality for this variant (Karchin 2008), increasing the likelihood this variant may have clinical significance. In one study (Surowy 2014), reviewing all evidence on p.Asn3124Ile variant, the authors investigated the potential pathogenic nature of the p.Asn3124Ile variant. The authors detected the variant in seven families with high-risk familial breast and other related cancers. The absence of this variant in more than 3,000 control individuals of the same geographical region, its absence in individuals with breast cancer with pathogenic BRCA1/2 mutations, its co-segregation with breast and ovarian cancer in one first degree relative in one family, and consistent results of in silico prediction analyses confirm the strong association with high breast cancer risk and underline that the BRCA2 p.Asn3124Ile variant is most likely a pathogenic mutation. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
CZECANCA consortium RCV001271066 SCV001451891 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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