ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.122A>T (p.His41Leu) (rs80357276)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221074 SCV000274542 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing The p.H41L variant (also known as c.122A>T), located in coding exon 2 of the BRCA1 gene, results from an A to T substitution at nucleotide position 122. The histidine at codon 41 is replaced by leucine, an amino acid with similar properties. Substitutions at this amino acid residue severely impact E3 ubiquitin ligase activity, however, they have minimal impact on BARD1 binding (Morris JR et al. Hum Mol Genet. 2006 Feb;15(4):599-606; Starita LM et al. Genetics, 2015 Jun;200:413-22). Several other substitutions at this amino acid position are pathogenic, including arginine and tyrosine (Ambry internal data; 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). This variant affects a known zinc binding motif which is predicted to disrupt protein folding (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol., 2001 Oct;8:833-7; Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A., 2003 May;100:5646-51). 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 variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238698 SCV000296354 uncertain significance Breast-ovarian cancer, familial 1 2016-04-12 criteria provided, single submitter clinical testing
GeneDx RCV000484008 SCV000564710 likely pathogenic not provided 2017-07-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.122A>T at the cDNA level, p.His41Leu (H41L) at the protein level, and results in the change of a Histidine to a Leucine (CAC>CTC). Using alternate nomenclature, this variant would be defined as BRCA1 241A>T. Functional interrogation of BRCA1 His41Leu by yeast-hybrid assay demonstrates impaired interaction between the variant and E2 (UbcH5a) in comparison to wild type (Morris 2006). In addition, a less severe, conservative amino acid change BRCA1 His41Arg (H41R) was predicted to be pathogenic by a multifactorial model based on pathology, species conservation and familial co-segregation, was deficient in a single strand annealing assay, has been associated with centrosome amplification, was non-functional in a homology-directed recombination (HDR) assay and exhibited decreased BARD1 binding and ubiquitin ligase activity (Whiley 2014, Towler 2013, Kais 2012, Ransburgh 2010, Morris 2006). BRCA1 His41Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 His41Leu occurs at a position that is conserved in mammals and is located in the RING-finger domain and Ub site, as well as a region known to interact with multiple other proteins (Wu 1996, Narod 2004, Borg 2010, Harte 2010, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRCA1 His41Leu to be a likely pathogenic variant.
Counsyl RCV000238698 SCV000784758 uncertain significance Breast-ovarian cancer, familial 1 2017-11-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000221074 SCV001348623 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194451 SCV001364030 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-10-17 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.122A>T (p.His41Leu) 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 250784 control chromosomes. c.122A>T has been reported in the literature in one individual affected with Breast Cancer (Tung_2014). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant is non-functional in a homology-directed DNA repair assay. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2x likely pathogenic, 2x VUS). In addition, p.His41Arg and p.His41Tyr has been reported to associate with HBOC (HGMD). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001194451 SCV001392328 pathogenic Hereditary breast and ovarian cancer syndrome 2020-02-14 criteria provided, single submitter clinical testing This sequence change replaces histidine with leucine at codon 41 of the BRCA1 protein (p.His41Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 230862). This variant has been reported to affect BRCA1 protein function (PMID: 30209399, 30219179, 25823446). This variant disrupts the p.His41 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20103620, 21725363, 24489791, 30209399, 25823446). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001292947 SCV001481655 likely pathogenic Fanconi anemia, complementation group S 2020-01-13 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 25186627, 30209399]
Brotman Baty Institute,University of Washington RCV000238698 SCV001237887 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.