ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.122A>G (p.His41Arg) (rs80357276)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569789 SCV000660995 likely pathogenic Hereditary cancer-predisposing syndrome 2016-04-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA1) RCV000111820 SCV000144373 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000111820 SCV000324990 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000111820 SCV000244297 pathogenic Breast-ovarian cancer, familial 1 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 = 0.995
GeneDx RCV000484980 SCV000568437 pathogenic not provided 2016-05-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.122A>G at the cDNA level, p.His41Arg (H41R) at the protein level, and results in the change of a Histidine to an Arginine (CAC>CGC). Using alternate nomenclature, this pathogenic variant would be defined as BRCA1 241A>G. This variant has been observed in at least one individual with breast cancer (Kawahara 2004). BRCA1 His41Arg has been associated with weakened BARD1 binding, centrosome amplification, and inhibition of ubiquitin ligase, single strand annealing (SSA), and homology directed recombination (HDR) activities (Morris 2006, Ransburgh 2010, Kais 2012, Towler 2013). Additionally, this variant was predicted to be pathogenic by a multifactorial model based on tumor pathology, segregation, and in silico analyses (Whiley 2014). BRCA1 His41Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA1 His41Arg occurs at a position that is conserved in mammals and at an important zinc-ligating residue located within the RING domain and the binding domains of BARD1 and BRD7 (Narod 2004, Borg 2010, Harte 2010, Paul 2014). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel classifies this variant as pathogenic (ClinVar). Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000047383 SCV000916704 pathogenic Hereditary breast and ovarian cancer syndrome 2018-01-25 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.122A>G (p.His41Arg) variant involves the alteration of a conserved nucleotide located in the Zinc finger, C3HC4 RING-type domain (IPR018957) (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. Functional studies reported that this variant showed abrogated function in the homology directed repair assay, abrogated ubiquitin ligase and weak BARD1 binding activity (Morris_2006, Towler_2013, Ransburgh_2010). This variant is absent in 245588 control chromosomes in gnomAD and was reported in multiple breast cancer patients (Whiley_2014, Kawahara_2004, Tung_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000047383 SCV000075396 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-13 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 41 of the BRCA1 protein (p.His41Arg). 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 families affected with breast cancer (PMID: 15168169, 24489791). ClinVar contains an entry for this variant (Variation ID: 54166). Experimental studies have shown that this missense change affects a zinc-coordinating residue in the RING domain of the BRCA1 protein, leading to loss of ubiquitin ligase activity, as well as defective repair of double-stranded DNA breaks, and centrosome amplification (PMID: 16403807, 23161852, 20103620, 21725363). Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 24489791). In summary, this variant has been reported in affected individuals and leads to defective BRCA1 function. However, without additional genetic data, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484980 SCV000600243 likely pathogenic not provided 2016-08-22 criteria provided, single submitter clinical testing

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