ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.53T>C (p.Met18Thr) (rs80356929)

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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) RCV000031245 SCV001161644 pathogenic Breast-ovarian cancer, familial 1 2019-06-18 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 = 0.99829
Ambry Genetics RCV000131693 SCV000186729 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-17 criteria provided, single submitter clinical testing The p.M18T variant (also known as c.53T>C), located in coding exon 1 of the BRCA1 gene, results from a T to C substitution at nucleotide position 53. The methionine at codon 18 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in multiple early-onset breast and ovarian cancer patients to date and has been associated with a significant reduction in homologous-directed recombination activity compared with wild type BRCA1 (p<0.001) (Langston AA et al. N. Engl. J. Med. 1996; 334:137-42, Greenman J et al. Genes Chromosomes Cancer 1998; 21:244-9, Malone KE et al. JAMA 1998; 279:922-9, Ransburgh DJ et al. Cancer Res., 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013; 34:439-45). This alteration also demonstrated reduced ubiquitin ligase activity and BARD1 binding activity as compared to wild type (Whiley PJ et al. PLoS ONE, 2014 Jan;9:e86836; Starita LM et al. Genetics. 2015 Jun;200(2):413-22). An additional 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). The p.M18T alteration has been classified as likely pathogenic (p>0.95) 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, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8). 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.
GeneDx RCV000212154 SCV000210063 likely pathogenic not provided 2018-08-18 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.53T>C at the cDNA level, p.Met18Thr (M18T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). Using alternate nomenclature, this variant would be defined as BRCA1 172T>C. BRCA1 Met18Thr has been observed in multiple individuals with breast or ovarian cancer, including male breast cancer (Langston 1996, Greenman1998, Malone 1998, van Orsouw 1999), and was reported to segregate with disease in two kindreds (Mohammadi 2009). This variant was predicted by Lindor et al. (2012) to likely be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. Functional studies have found discordant results with respect to ubiquitin ligase activity and BARD1 binding, but have revealed impaired homology-directed repair activity, increased centrosome amplification, and loss of ability to rescue cell growth (Ruffner 2001, Morris 2004, Morris 2006, Sarkar 2008, Ransburgh 2010, Parvin 2011, Kais 2012, Bouwman 2013, Towler 2013, Starita 2015). BRCA1 Met18Thr was not observed in large population cohorts (Lek 2016). This variant is located in the RING domain and a region that binds 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 information, we consider BRCA1 Met18Thr to be a likely pathogenic variant.
Counsyl RCV000031245 SCV000786080 likely pathogenic Breast-ovarian cancer, familial 1 2018-02-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131693 SCV000909428 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-15 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001253789 SCV001429658 pathogenic Hereditary breast and ovarian cancer syndrome 2019-02-14 criteria provided, single submitter clinical testing Data included in classification: The variant was observed in 7 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 25,773. Case control comparison against ethnically matched population data (7/25,773 in familial cases against 0/56,696 GNOMAD NFE controls pexact= 0.00029 (PS4_VS). The variant is absent in the remainder of the GNOMAD populations (68,846 individuals) (PM2_mod). Non-functional in SGE haploid BRCA1-assay (Findlay et al. 2018) (PS3_strong). Classified as Likely Pathogenic by Ambry 2018, Gene Dx 2014, Counsyl 2018 Color LP 2018 (PP5_sup). Data not included in classification: Predicted deleterious on SIFT and Align GVGD. Predicted benign on Polyphen HumVar. There are additional reports of this variant in ClinVar (5), BIC (3) and BRCA1 LOVD (11), UMD(7), DMuDB(7).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001253789 SCV001478704 pathogenic Hereditary breast and ovarian cancer syndrome 2021-01-07 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.53T>C (p.Met18Thr) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of 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 254472 control chromosomes (ACMG, PM2). c.53T>C has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (ACMG, PS4). These data indicate that the variant is very likely to be associated with disease. In functional analyses, multiple studies have reported deleterious effects of the variant, including centrosome amplification, defective BRCA1-mediated homologous repair, defective double-strand break repair, and defective homology-directed recombination (HDR) (Kais_2013, Parvin_2011, Ransburgh_2010, Towler_2013) (ACMG, PS3). In addition, multifactorial probability models have predicted the variant to be likely pathogenic or pathogenic (Lindor_2012, Easton_2007, Parsons_2019). Six submitters including an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001253789 SCV001575134 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-05-14 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 18 of the BRCA1 protein (p.Met18Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with breast and/or ovarian cancer (PMID: 9544766, 10528853, 16683254, 9523200, 8531967). This variant is also known as c.172T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 37664). Experimental studies have shown that this missense change affects different aspects of the BRCA1 function: homologous recombination activity, ubiquitin ligase activity, centrosome amplification, single strand annealing and cisplatin sensibility (PMID: 27272900, 20103620, 21725363, 25823446, 23867111, 23161852). Moreover, based on multifactorial likelihood algorithms using genetic, clinical, in silico, or statistical data, this variant has been determined to have a hight probability of being pathogenic (PMID:17924331, 21990134, 19563646, 24489791). 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.
Sharing Clinical Reports Project (SCRP) RCV000031245 SCV000053849 likely pathogenic Breast-ovarian cancer, familial 1 2011-04-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031245 SCV000144142 uncertain significance Breast-ovarian cancer, familial 1 1999-03-24 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000031245 SCV001237745 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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