ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs28897759
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Total submissions: 41
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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, susceptibility to, 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
Labcorp Genetics (formerly Invitae), Labcorp RCV000045802 SCV000073815 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3124 of the BRCA2 protein (p.Asn3124Ile). This variant is present in population databases (rs28897759, gnomAD 0.002%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11102977, 16284991, 18703817, 21120943, 21232165, 21965345, 22366370, 22729890, 25948282). It is commonly reported in individuals of Polish and German ancestry (PMID: 11802209, 20383589, 24728577, 25948282). This variant is also known as 9599A>T and p. Asn312lle. ClinVar contains an entry for this variant (Variation ID: 38233). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 22678057, 23108138). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000130337 SCV000185187 pathogenic Hereditary cancer-predisposing syndrome 2021-08-13 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 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; Alemar B et al. PLoS One, 2017 Nov;12:e0187630; Meisel C et al. Arch Gynecol Obstet. 2017 May;295(5):1227-1238; Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165; Kowalik A et al. PLoS One, 2018 Jul;13:e0201086; Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant was also reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Eurofins Ntd Llc (ga) RCV000505786 SCV000228185 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000505786 SCV000278888 pathogenic not provided 2023-12-18 criteria provided, single submitter clinical testing Observed in individuals with BRCA2-related cancers and described as a recurrent pathogenic variant in the Eastern European population (PMID: 11139248, 21965345, 20383589, 22366370, 24728577, 25452441, 25948282, 26786923, 26843898, 29161300); Published functional studies demonstrate a damaging effect: defective homology-directed DNA break repair, impaired protein structure and stability, and sensitivity to PARP inhibitors (PMID: 22678057, 23108138, 29394989, 29884841, 32444794, 33964450, 33609447, 35736817); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9599A>T; This variant is associated with the following publications: (PMID: 24323938, 21965345, 16284991, 20383589, 11102977, 22366370, 28888541, 29161300, 11139248, 22729890, 21232165, 25782689, 26843898, 25948282, 23108138, 26219265, 25452441, 22678057, 21120943, 26689913, 18724707, 19043619, 23583677, 11452040, 24728577, 26786923, 27153395, 28324225, 28873162, 25085752, 11802209, 28715532, 29387975, 29506128, 29394989, 31131967, 29907814, 29988080, 29446198, 31159747, 29884841, 32444794, 34597585, 34426522, 34399810, 30787465, 30613976, 31360904, 33964450, 33609447, 35665744, 35736817, 35264596, 30040829, 29922827, 32772980, 12228710, 27535533, 21990134)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031816 SCV000328117 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000031816 SCV000593759 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2016-02-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505786 SCV000600859 pathogenic not provided 2021-05-28 criteria provided, single submitter clinical testing This variant has been reported in individuals and families with breast and/or ovarian cancer in the published literature (PMID: 24728577 (2014), 25085752 (2014), 22729890 (2012) and 11139248 (2001)). In addition, functional studies in the published literature demonstrate that this variant is damaging to BRCA2 protein function (PMID: 32444794 (2020), 23108138 (2013), 22678057 (2012), and 22729890 (2012)). Publications describe this variant as recurrent pathogenic variant in the Polish population (PMID: 28324225 (2017) and 26843898 (2016)). Based on the available information, this variant is classified as pathogenic.
Counsyl RCV000031816 SCV000677707 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2016-06-17 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000130337 SCV000684058 pathogenic Hereditary cancer-predisposing syndrome 2023-02-28 criteria provided, single submitter clinical testing This missense variant replaces asparagine with isoleucine at codon 3124 in the DNA binding domain of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of homology-directed repair activity of the BRCA2 protein (PMID: 22678057, 23108138, 29394989, 29988080, 33609447, 33964450). This variant has been reported in more than 20 individuals affected with breast cancer and ovarian cancer (PMID: 11102977, 11139248, 11802209, 20383589, 21232165, 21965345, 22366370, 24728577, 26786923, 26843898, 27616075, 30040829, 34399810). This variant has shown a significant association with breast cancer in a large case-control study conducted by the BRIDGES consortium (14/60466 cases, 1/53461 controls; OR=12.381 (95%CI 1.628 to 94.157); p-value=0.001; Leiden Open Variation Database DB-ID BRCA2_000450). This variant has been identified in 1/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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 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, susceptibility to, 2 2017-07-28 criteria provided, single submitter clinical testing
Mendelics RCV000031816 SCV001139258 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000031816 SCV001429468 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2023-11-21 criteria provided, single submitter clinical testing Criteria applied: PS3,PS4,PP3
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 and Genomics, 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 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, susceptibility to, 1 2020-04-02 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000505786 SCV001502177 pathogenic not provided 2024-04-01 criteria provided, single submitter clinical testing BRCA2: PP1:Strong, PS4, PM2, PM5, PS3:Supporting
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000505786 SCV002010289 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000505786 SCV002021452 pathogenic not provided 2022-10-01 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000585706 SCV002579226 pathogenic Familial cancer of breast 2021-08-26 criteria provided, single submitter clinical testing
Human Genetics Bochum, Ruhr University Bochum RCV000031816 SCV002758605 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2022-02-04 criteria provided, single submitter clinical testing ACMG criteria used to clasify this variant: PP3, PS3, PM1, PS4, PM2
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000031816 SCV002764934 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2021-12-21 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001310163 SCV003921103 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-02-07 criteria provided, single submitter clinical testing Criteria applied: PP4_VSTR,PS3
Baylor Genetics RCV000585706 SCV004216055 pathogenic Familial cancer of breast 2023-12-19 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000585706 SCV004698053 pathogenic Familial cancer of breast 2024-05-13 criteria provided, single submitter clinical testing Criteria applied: PP1_VSTR,PS3
All of Us Research Program, National Institutes of Health RCV000031816 SCV004846161 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2024-01-08 criteria provided, single submitter clinical testing This missense variant replaces asparagine with isoleucine at codon 3124 in the DNA binding domain of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of homology-directed repair activity of the BRCA2 protein (PMID: 22678057, 23108138, 29394989, 29988080, 33609447, 33964450). This variant has been reported in more than 20 individuals affected with breast cancer and ovarian cancer (PMID: 11102977, 11139248, 11802209, 20383589, 21232165, 21965345, 22366370, 24728577, 26786923, 26843898, 27616075, 30040829, 34399810). This variant has shown a significant association with breast cancer in a large case-control study conducted by the BRIDGES consortium (14/60466 cases, 1/53461 controls; OR=12.381 (95%CI 1.628 to 94.157); p-value=0.001; Leiden Open Variation Database DB-ID BRCA2_000450). This variant has been identified in 1/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Department of Human Genetics, Hannover Medical School RCV000031816 SCV005201121 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2024-09-10 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031816 SCV000054424 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2013-07-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031816 SCV000147620 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 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 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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000505786 SCV001743985 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000505786 SCV001906139 likely pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000505786 SCV001957664 pathogenic not provided no assertion criteria provided clinical testing
BRCAlab, Lund University RCV000031816 SCV002588940 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2022-08-26 no assertion criteria provided clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas RCV000031816 SCV004171674 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2023-11-24 no assertion criteria provided clinical testing
Department of Medical and Surgical Sciences, University of Bologna RCV000031816 SCV004228299 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2023-09-01 no assertion criteria provided clinical testing PS3(Strong)+PM2(Supporting)+PP4(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)

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