ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.65T>C (p.Leu22Ser) (rs80357438)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000083224 SCV000244409 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 = 0.99
Invitae RCV000049081 SCV000077094 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-09-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 22 of the BRCA1 protein (p.Leu22Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 9609997, 19543972, 25452441). ClinVar contains an entry for this variant (Variation ID: 55656). An experimental study demonstrated that this missense change affects the homology-directed DNA repair activity of the BRCA1 protein (PMID: 25823446). However, a different study reported contradictory results when evaluating the effects of this missense variant in multiple assays (PMID: 27272900). In addition, a multifactorial likelihood algorithm using genetic and functional data suggests this variant has been determined to have a high probability of being pathogenic (PMID: 21990134). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000162704 SCV000213164 likely pathogenic Hereditary cancer-predisposing syndrome 2017-09-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Counsyl RCV000083224 SCV000220976 pathogenic Breast-ovarian cancer, familial 1 2014-12-22 criteria provided, single submitter literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083224 SCV000326372 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000083224 SCV000564345 likely pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000479212 SCV000568441 likely pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.65T>C at the cDNA level, p.Leu22Ser (L22S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). Using alternate nomenclature, this variant has been published as BRCA1 184T>C. This variant was observed in individuals with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (Katagiri 1998, Sweet 2010, Couch 2015, Fernandes 2016, Pilato 2016, Lowery 2018). Several functional studies have suggested that BRCA1 Leu22Ser is pathogenic based on E3 ubiquitin ligase ability, HDR rescue, colony size, and liquid medium function, while other functional assays demonstrated BARD1 binding, spot formation, and yeast localization comparable to wild-type (Starita 2015, Thouvenot 2016). BRCA1 Leu22Ser was strongly predicted to be pathogenic based on several multifactorial models incorporating tumor characteristics and pathology, clinical histories, family studies, and co-occurrence with deleterious mutations (Sweet 2010, Lindor 2012, Vall?e 2012). BRCA1 Leu22Ser was not observed in large population cohorts (Lek 2016). BRCA1 Leu22Ser is located within the RING domain and a region known to interact with BRD7 and BARD1 (Narod 2004, Borg 2010, Harte 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider BRCA1 Leu22Ser to be a likely pathogenic variant.
Color RCV000162704 SCV000912062 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000049081 SCV000916786 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-12-14 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.65T>C (p.Leu22Ser) variant involves the alteration of a conserved nucleotide located in the Zinc finger, RING/FYVE/PHD-type (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 245708 control chromosomes, and has been reported in numerous affected individuals in the literature. Additionally, functional evidence has shown the variant to result in reduced HDR levels (Starita_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000083224 SCV000115298 uncertain significance Breast-ovarian cancer, familial 1 2009-10-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083224 SCV000144166 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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