ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7868A>G (p.His2623Arg) (rs80359012)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131271 SCV000186239 likely pathogenic Hereditary cancer-predisposing syndrome 2017-06-27 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,Structural Evidence,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Deficient protein function in appropriate functional assay(s)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031705 SCV000147205 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000131271 SCV000904991 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000480661 SCV000592153 uncertain significance not specified 2016-03-23 criteria provided, single submitter clinical testing
GeneDx RCV000505960 SCV000566558 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7868A>G at the cDNA level, p.His2623Arg (H2623R) at the protein level, and results in the change of a Histidine to an Arginine (CAC>CGC). Using alternate nomenclature, this variant would be defined as BRCA2 8096A>G. This variant was observed in at least two individuals with a personal and/or family history of breast and/or ovarian cancer (Foley 2015). BRCA2 His2623Arg was not observed in large population cohorts (Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 His2623Arg occurs at a position that is conserved across species and is located in 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, it is unclear whether BRCA2 His2623Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000480661 SCV000917059 uncertain significance not specified 2018-12-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7868A>G (p.His2623Arg) results in a non-conservative amino acid change located in the helical domain (IPR015252) that is part of the DNA binding domain (PMID: 22193408) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant was also predicted to be 'likely deleterious' by a protein likelihood ratio model (Karchin 2008). The variant was absent in 246040 control chromosomes (gnomAD). c.7868A>G has been reported in the literature in two high-risk individuals, one of them being affected with Breast Cancer (Foley 2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating a deleterious outcome for the variant in a homology-directed DNA repair (HDR) assay (Guidugli_BRCA_AJHG_2018). Multiple laboratories reported the variant with conflicting assessments (3 calling it VUS, and 2 classifying it as Likely Pathogenic). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000045333 SCV000073346 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 2623 of the BRCA2 protein (p.His2623Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two high-risk individuals for breast and ovarian cancer (PMID: 26023681). ClinVar contains an entry for this variant (Variation ID: 38123). Experimental studies have shown that this missense change disrupts BRCA2 homology-directed repair (HDR) activity (PMID: 23108138, 29394989). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505960 SCV000600769 likely pathogenic not provided 2017-03-11 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000480661 SCV000587916 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031705 SCV000054312 likely pathogenic Breast-ovarian cancer, familial 2 2010-04-12 no assertion criteria provided clinical testing

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