Submissions for variant NM_007294.4(BRCA1):c.122A>G (p.His41Arg)

dbSNP: rs80357276

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111820	SCV000244297	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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
Invitae	RCV000047383	SCV000075396	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 16403807, 20103620, 21725363, 22843421, 23161852, 25823446, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 54166). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15168169, 24489791). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 41 of the BRCA1 protein (p.His41Arg).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111820	SCV000324990	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484980	SCV000600243	likely pathogenic	not provided	2016-08-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569789	SCV000660995	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-28	criteria provided, single submitter	clinical testing	The p.H41R pathogenic mutation (also known as c.122A>G), located in coding exon 2 of the BRCA1 gene, results from an A to G substitution at nucleotide position 122. The histidine at codon 41 is replaced by arginine, an amino acid with highly similar properties. This histidine is crucial in coordinating the Zinc atom, which controls the structure of the functionally important RING domain (Brzovic PS et al. Nat. Struct. Biol. 2001 Oct; 8(10):833-7; Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May; 100(10):5646-51). Several independent functional assays demonstrate that although this alteration may not disrupt binding of BRCA1 to BARD1, it significantly impacts its ubiquitin ligase activity, homology directed recombination activity, single strand annealing abilities and significantly increased centrosome amplification (Morris JR et al. Hum. Mol. Genet. 2006 Feb; 15(4):599-606; Ransburgh DJ et al. Cancer Res. 2010 Feb; 70(3):988-95; Towler WI et al. Hum. Mutat. 2013 Mar; 34(3):439-45; Caleca L et al. Cancers (Basel), 2019 Jan;11; Starita LM et al. Genetics, 2015 Jun;200:413-22; Starita LM et al. Am. J. Hum. Genet., 2018 Oct;103:498-508). In support of these defects being inconsistent with normal BRCA1 function, a high throughput genome editing haploid cell survival assay also found this alteration deleterious (Findlay GM et al. Nature, 2018 10;562:217-222). In a study that used multifactorial likelihood analysis to assess the pathogenicity of BRCA1/2 variants, this variant was considered pathogenic with a posterior probability of pathogenicity of 0.995, largely attributable to a strong co-segregation likelihood ratio (Whiley PJ et al. PLoS ONE 2014; 9(1):e86836; Park KS et al. Genet. Med., 2016 12;18:1250-1257). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047383	SCV000916704	pathogenic	Hereditary breast 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000484980	SCV001449979	pathogenic	not provided	2019-12-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000111820	SCV004216834	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-02-14	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111820	SCV000144373	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111820	SCV001237886	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro