ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.134A>C (p.Lys45Thr) (rs80356863)

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
Invitae RCV000047432 SCV000075445 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 45 of the BRCA1 protein (p.Lys45Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. It also falls at the last nucleotide of exon 3 of the BRCA1 coding sequence. This variant is present in population databases (rs80356863, ExAC 0.003%). This variant has been reported in an individual affected with breast cancer (PMID: 20104584) and in individuals in the Breast Cancer Information Core (BIC) database (PMID: 10923033). However, a pathogenic allele was identified in the BRCA2 gene, which suggests that this c.134A>C substitution in BRCA1 was not the primary cause of disease in one of the individuals in the BIC database. ClinVar contains an entry for this variant (Variation ID: 37402). Experimental studies have shown that this missense change disrupts ubiquitin ligase activity of the BRCA1/BARD1 heterodimer in vitro (PMID: 16403807). Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681) but according to multiple splice site algorithms this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. In summary, this rare variant disrupts protein function in vitro and has been observed in affected individuals. However, it co-occurred with a pathogenic BRCA2 variant that likely explained one patient's condition. For these reasons, this change has been classified as a Variant of Uncertain Significance.
GeneDx RCV000585902 SCV000210060 uncertain significance not provided 2017-07-11 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.134A>C at the cDNA level, p.Lys45Thr (K45T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). This variant, also known as BRCA1 c.253A>C by alternate nomenclature, has been observed in at least two individuals with breast cancer and was shown to disrupt the interaction with the E2 enzyme and inhibit ubiquitin ligase activity in a yeast based in-vitro functional assay (Morris 2006, Borg 2010, Capanu 2011). BRCA1 Lys45Thr was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Lys45Thr occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located within the RING-finger domain Ub site, and a region known to interact with multiple other proteins (Wu 1996, Borg 2010, Paul 2014). In house in silico analyses predict that this variant is probably damaging to protein structure and function, while published computational models are inconsistent (Abkevich 2004, Pavlicek 2004). Additionally, this variant is located in the last nucleotide of exon 3. While in-house splicing models predict no effect on splicing, a published computational model predicts this variant to weaken the natural splice donor site (Mucaki 2011); however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA1 Lys45Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000166686 SCV000217494 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000030983 SCV000488132 uncertain significance Breast-ovarian cancer, familial 1 2016-02-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212155 SCV000600248 uncertain significance not specified 2016-11-04 criteria provided, single submitter clinical testing
Color RCV000166686 SCV000688332 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585902 SCV000698849 uncertain significance not provided 2016-08-22 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.134A>C (p.Lys45Thr) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant. This variant is located in the RING domain (InterPro, UniProt). This variant was found in 2/111480 control chromosomes from ExAC, only observed in the European (Non-Finnish) subpopulation at a frequency of 0.0000328 (2/61036). This frequency is about lower than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in at least four affected patients from HBOC families from literature (Borg_2010) and clinical database (BIC). There are no co-segregation studies for the variant. In one of the patients reported by BIC, this variant co-occurred with a deleterious variant in BRCA2 c.26_26delC (p.Pro9Glnfs), suggesting that it is not a primary cause of disease in the patient. From a yeast based in-vitro functional assay, this variant was shown to disrupt the interaction with the E2 enzyme and abrogate ubiquitin ligase activity (Morris_2006), strongly suggesting that it leads to functional impairment of BRCA1 protein. However, there are no other replicative functional studies. There are two other missense variants reported at this residue: p.Lys45Asn and p.Lys45Gln; while p.Lys45Asn is of uncertain significance and p.Lys45Gln is benign as per submitters in ClinVar. Multiple clinical diagnostic laboratories/reputable databases classified this variant of interest as uncertain significance. Taken together, based on some conflicts and lack of sufficient evidences to prove the variants pathogenicity, it is currently classified as a variant of uncertain significance (VUS).
Sharing Clinical Reports Project (SCRP) RCV000030983 SCV000053575 uncertain significance Breast-ovarian cancer, familial 1 2010-05-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000030983 SCV000144426 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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.