ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.122A>T (p.His41Leu) (rs80357276)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221074 SCV000274542 likely pathogenic Hereditary cancer-predisposing syndrome 2017-10-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Structural Evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other data supporting pathogenic classification
Counsyl RCV000238698 SCV000784758 uncertain significance Breast-ovarian cancer, familial 1 2017-11-21 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.
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

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