ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7879A>T (p.Ile2627Phe) (rs80359014)

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Total submissions: 20
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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) RCV000077415 SCV000244476 pathogenic Breast-ovarian cancer, familial 2 2015-08-10 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 RCV000045337 SCV000073350 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 2627 of the BRCA2 protein (p.Ile2627Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families with breast and/or ovarian cancer (PMID: 10699917, 20104584, 21232165, 20383589, 25452441, 29335924), as well as in an individual affected with prostate cancer (PMID: 29368341). It is also known as 8107A>T in the literature. ClinVar contains an entry for this variant (Variation ID: 52430). This variant is located in the DNA-binding domain (DBD) of the BRCA2 protein (PMID: 18451181). Experimental studies have shown that this variant affects BRCA2 homology-directed repair activity, regulation of centrosome amplification, and complementation of the lethality in BRCA2-deficient cells (PMID: 18451181, 23108138, 25146914, 29884841, 29394989). Multifactorial likelihood analyses based on genetic data using family history, co-segregation, and co-occurrence predict that this variant has a high probability of being deleterious (PMID: 17924331, 18451181, 21990134, 23108138). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131675 SCV000186711 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-04 criteria provided, single submitter clinical testing The p.I2627F variant (also known as c.7879A>T), located in coding exon 16 of the BRCA2 gene, results from an A to T substitution at nucleotide position 7879. The isoleucine at codon 2627 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been classified as pathogenic (p>0.99) 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, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8; Lindor NM et al. Hum. Mutat. 2012;33(1):8-21; Hendriks G et al. Hum. Mutat. 2014;35(11):1382-91). In multiple studies, this alteration was detected in several individuals with breast or ovarian cancer (Spitzer E et al. Int. J. Cancer 2000;85(4):474-81; Balabas<span style="font-family:sans-serif,arial,verdana,trebuchet ms"> A et al. Fam. Cancer<span style="font-family:sans-serif,arial,verdana,trebuchet ms"> 2010;9(3):267-74; Stegel V et al. BMC Med. Genet. 2011;12():9; Kluska A et al. BMC Med Genomics 2015;8():19; Couch FJ et al. J. Clin. Oncol. 2015;33(4):304-11; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Zakrzewski F et al. BMC Cancer 2019 Apr;19(1):396). A homology-directed DNA repair (HDR) assay demonstrated p.I2627F to have low functionality, with a probability of pathogenicity of 0.990 (Guidugli L et al. Am. J. Hum. Genet. 2018 Feb;102(2):233-248). In addition, a mouse embryonic stem cell assay showed that p.I2627F was unable to complement Brca2-deficient cell lethal phenotype (Mesman R et al. Genet. Med. 2019 02;21(2):293-302). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Michigan Medical Genetics Laboratories,University of Michigan RCV000077415 SCV000267813 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
GeneDx RCV000218666 SCV000278877 pathogenic not provided 2017-08-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7879A>T at the cDNA level, p.Ile2627Phe (I2627F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATC>TTC). Using alternate nomenclature, this variant has been previously published as BRCA2 8107A>T. BRCA2 Ile2627Phe has been observed in multiple breast/ovarian cancer families (Spitzer 2000, Balabas 2010, Stegel 2011, Lee 2014, Meisel 2017), and was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. Functional studies demonstrated that BRCA2 Ile2627Phe displayed both reduced homology directed repair activity and an increase in centriole amplification when compared to wild-type, suggesting a disruption of BRCA2 function (Farrugia 2008, Guidugli 2013). BRCA2 Ile2627Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile2627Phe occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, we consider BRCA2 Ile2627Phe to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077415 SCV000296502 likely pathogenic Breast-ovarian cancer, familial 2 2016-05-30 criteria provided, single submitter clinical testing
GeneKor MSA RCV000218666 SCV000296832 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This variant results in the substitution of Isoleucine to Phenylalanine at amino acid residue 2627 of the BRCA2 protein. The Isoleucine residue is highly conserved among species and is located in a functional domain of the protein and there is a small physiochemical difference between Isoleucine and Phenylalanine (Grantham Score 21). This variant has been reported in the literature in patients and families with breast and/or ovarian cancer (PMID: 10699917, 20104584, 25452441). Also, this variant has been described as 8107A>T in the literature and is absent in population databases (rs80359014). The mutation database ClinVar contains entries for this variant (Variation ID: 52430). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein and this prediction has also been observed experimentally. Experimental studies have shown that this variant affects BRCA2 homology-directed repair activity while loss of the protein function results in cell death (PMID: 18451181, 23108138, 25146914).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077415 SCV000327756 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131675 SCV000683913 pathogenic Hereditary cancer-predisposing syndrome 2020-06-22 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with phenylalanine at codon 2627 in the DNA binding domain of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant 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 DNA repair activity (PMID: 18451181, 23108138). This variant has been reported in over ten individuals affected with breast cancer (PMID: 10699917, 20104584, 20383589, 21520273, 29335924) and prostate cancer (PMID: 29368341). Multifactorial likelihood analyses based on clinical observations from multiple families have determined this variant to be disease-causing (PMID: 17924331, 18451181). Of note, this variant has been observed in six breast cancer-affected individuals of Macedonian origin, who showed significant family history of BRCA2-related cancers (PMID: 29335924). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763326 SCV000894003 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000218666 SCV001249494 pathogenic not provided 2020-09-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045337 SCV001338376 pathogenic Hereditary breast and ovarian cancer syndrome 2020-02-21 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7879A>T (p.Ile2627Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251356 control chromosomes. c.7879A>T has been well reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer in literature spanning over ten years to include multifactorial probability models for assessing pathogenic outcomes (example, Borg_2010, Capanu_2011, Stegel_2011, Spitzer_2000, Kluska_2015, Couch_2015, Rebbeck_2018, Lindor_2012, Easton_2007). These data indicate that the variant is very likely to be associated with disease. At-least one co-occurrence with another pathogenic variant has been reported in a patient with triple negative breast cancer (PALB2 c.2470dupT, p.Cys824LeufsX2)(Couch_2015). However, this does not rule out the pathogenicity of this variant due to the possibility of mutual exclusivity of the two variants. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an inability to complement the lethality of mBRCA2-deficient mouse-embryonic stem (mES) cells (example, Hendriks_2014 and Mesman_2019) as well as decreased homology directed repair activity (example, Farrugia_2008, Guidguli_2012). One expert panel (ENIGMA) and ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic (n=8)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000077415 SCV001428833 pathogenic Breast-ovarian cancer, familial 2 2018-12-04 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000218666 SCV001447781 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077415 SCV000109213 pathogenic Breast-ovarian cancer, familial 2 2012-03-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077415 SCV000147209 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 RCV000045337 SCV000587918 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000218666 SCV000592155 pathogenic not provided no assertion criteria provided clinical testing The p.Ile2627Phe variant was identified in 1 of 4206 proband chromosomes (frequency: 0.0001) from individuals or families with bilateral and unilateral breast cancer (Borg 2010); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was identified in dbSNP (ID: rs80359014) “With Pathogenic, Uncertain significance allele.” The p.Ile2627Phe variant was also identified in GeneInsight COGR database by 2 submitters, one classified as pathogenic and the other as VUS. In Clinvar database, the variant was identified and classified as pathogenic by ENIGMA and by the Sharing Clinical Reports Project, derived from Myriad reports; it was classified as likely pathogenic by Ambry Genetics and no classification was provided by Invitae. The BRCA Share UMD Database identified the variant 1x and classified it as causal and ARUP Laboratories identified the variant 1x and classified it definitely pathogenic. In BIC database the variant was identified 7x with unknown clinical significance. The variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server) and Exome Aggregation Consortium (ExAC), COSMIC, Clinvitae or MutDB. The p.Ile2627 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phenylalanine (Phe) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In addition, Multifactorial likelihood-ratio modelling, homology-directed repair assay and centrosome percent amplification assay, suggest that the variant disrupts BRCA2 function (Farrugia 2008, Easton 2007). Studies on protein likelihood ratio modelling is in favour of protein loss of function (Karchin 2008) and based on multifactorial probability-based model for assessing pathogenicity, the prior probability of being deleterious is 0.29 and posterior probability of being deleterious 1.00 (Lindor 2012).In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
King Laboratory,University of Washington RCV001171395 SCV001251298 benign not specified 2019-09-01 no assertion criteria provided research
Department of Medical Laboratory Science, Faculty of Allied Health Sciences,University of Peradeniya RCV001289537 SCV001477299 pathogenic Familial cancer of breast 2019-10-19 no assertion criteria provided research

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