ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.65T>C (p.Leu22Ser) (rs80357438)

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Total submissions: 13
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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 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-04 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, 30339520). ClinVar contains an entry for this variant (Variation ID: 55656). This variant has been reported to affect BRCA1 protein function (PMID: 25823446, 30209399). In addition, based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 21990134). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000162704 SCV000213164 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-02 criteria provided, single submitter clinical testing The p.L22S variant (also known as c.65T>C), located in coding exon 1 of the BRCA1 gene, results from a T to C substitution at nucleotide position 65. The leucine at codon 22 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in Japanese, Ashkenazi Jewish, Brazilian, German, Norwegian, and Italian HBOC families (Katagiri T et al. J. Hum. Genet. 1998;43:42-8; Sweet K et al. Breast Cancer Res. Treat. 2010 Feb;119:737–43; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620; Palmero EI et al. Sci Rep, 2018 Jun;8:9188). This alteration has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Of note, this alteration is also designated as 184T>C in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 2019-10-22 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27225819, 25452441, 18951461, 24489791, 19543972, 25525159, 21990165, 24281179, 22753008, 9609997, 27272900, 25823446, 21990134, 28408614, 27741520, 29339979, 29506128, 29907814, 29446198, 30219179, 30209399, 33087888)
Color Health, Inc RCV000162704 SCV000912062 pathogenic Hereditary cancer-predisposing syndrome 2020-07-29 criteria provided, single submitter clinical testing This missense variant replaces leucine with serine at codon 22 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in loss of homology-directed recombination activity of BRCA1 protein (PMID: 25823446, 30219179, 30696104) and disrupts BARD1 binding activity (PMID: 30696104). This variant has been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in multiple individuals affected with breast and/or ovarian cancer (PMID: 9609997, 19543972, 27741520, 29907814, 32380732, 32438681) and pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Research and Development, ARUP Laboratories RCV001664167 SCV001877786 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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
Brotman Baty Institute,University of Washington RCV000083224 SCV001242257 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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