ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5339T>C (p.Leu1780Pro) (rs80357474)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048948 SCV000076961 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1780 of the BRCA1 protein (p.Leu1780Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families affected with hereditary breast and ovarian cancer, including segregation in a family (PMID: 15117986, 17100994, 22217648, 27124784, 27658390, 28364669, 28111427, 29020732, 29770616, 28288110, 27383479, 27488874), as well as in unaffected individuals (PMID: 17100994, 22217648, 27658390). ClinVar contains an entry for this variant (Variation ID: 55541). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 30415210). This variant has been reported to affect BRCA1 protein function (PMID: 10811118, 20516115, 20378548, 30209399). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000132201 SCV000187283 pathogenic Hereditary cancer-predisposing syndrome 2020-09-29 criteria provided, single submitter clinical testing The p.L1780P variant (also known as c.5339T>C), located in coding exon 20 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5339. The leucine at codon 1780 is replaced by proline, an amino acid with similar properties. This alteration has been detected in many Korean case reports and case-control studies of breast and/or ovarian cancer and is statistically significantly over-represented in the affected populations versus control populations (Choi DH et al. J. Clin. Oncol. 2004 May;22:1638-45; Han SH et al. Clin. Genet. 2006 Dec;70:496-501; Jang JH et al. J. Hum. Genet. 2012 Mar;57:212-5; Yoon KA et al. Cancer Res Treat. 2017 Jul;49:627-634; Eoh KJ et al. Cancer Res Treat. 2018 Jul;50:917-925; Park JS et al. Cancer Res Treat. 2017 Oct;49:1012-1021; Ryu JM et al. Breast. 2017 Jun;33:109-116; Choi MC et al. J Gynecol Oncol. 2018 Jul;29:e43). This variant segregated with disease in two of these studies and is also suggested to be a Korean founder mutation (Ryu JM et al. Breast. 2017 Jun;33:109-116; Park JS et al. Cancer Res Treat. 2017 Oct;49:1012-1021). Analysis of this alteration in yeast, bacterial and mammalian systems show that it is functionally deleterious in terms of cell survival, transcriptional activation, protein binding and protein folding (Findlay GM et al. Nature. 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Rowling PJ et al. J. Biol. Chem. 2010 Jun;285:20080-7; Hayes F et al. Cancer Res. 2000 May;60:2411-8). Of note, this alteration is also designated as 5458T>C in some published literature. This amino acid position is highly conserved on sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000236823 SCV000293458 likely pathogenic not provided 2018-02-06 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5339T>C at the cDNA level, p.Leu1780Pro (L1780P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). Using alternate nomenclature, this variant has been reported as BRCA1 5458T>C. This variant has been observed in multiple individuals of Korean ancestry with breast and/or ovarian cancer, as well as in several unaffected controls (Choi 2004, Han 2006, Jang 2012, Eoh 2016, Yoon 2016, Ryu 2017). In a study of Korean women with histories suspicious for Hereditary Breast and Ovarian Cancer, Park et al. (2017) calculated an odds ratio of 41.2 (95% CI 2.4-699.5), and suggest that BRCA1 Leu1780Pro is a pathogenic Korean founder variant. Hayes et al. (2000) demonstrated that this variant causes loss of transcription activation function in a yeast-based assay. Additionally, Lee et al. (2010) reported that this variant impacted protease sensitivity, binding activity and specificity, and transcription activity. BRCA1 Leu1780Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider BRCA1 Leu1780Pro to be a likely pathogenic variant.
Center for Breast Cancer,National Cancer Center RCV000048948 SCV000484656 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-05 criteria provided, single submitter clinical testing A total of 328 breast cancer patients underwent BRCA1/2 genetic screening at the National Cancer Center of Korea. The c.5339T>C variant in the BRCA1 gene was detected in four patients with a family history of breast cancer. It was not detected in 421 healthy controls. We were able to recruit family members of the proband harboring the c.5339T>C variant in the BRCA1 gene. As shown in the pedigree in the published article, two breast cancer patients in this family and the proband were also diagnosed with ovarian cancer 2 years after being diagnosed with breast cancer. The father of the proband also carried the same UV, and his sister died of breast cancer at the age of 46. Another patient who harbored the same variant was diagnosed with breast cancer at the age of 33. Her mother suffered from ovarian cancer and could not participate in this study. The c.5339T>C variant results in an amino acid change from leucine to proline at position 1780. The predicted structure shows that the mutation site is in the middle of a helix in the BRCT domain of BRCA1, forming a hydrophobic patch with its surrounding residues. The BRCT domain is known to recognize and bind phosphorylated pSXXF motifs of FAM175A/Abraxas to recruit BRCA1 to regions of DNA damage.
Cancer Prevention Center, Yonsei Cancer Center,Severance Hospital, Yonsei University College of Medicine RCV000112624 SCV000512304 pathogenic Breast-ovarian cancer, familial 1 2016-06-15 criteria provided, single submitter research We observed that 11 HBOC patients with L1780P variant showed typical clinicopathological feature of patients with BRCA1 mutations. When we apply the ACMG standards and guideline for reclassification of L1780P, L1780P is a highly suspected of pathogenic varints of BRCA1. A previous study (Lee et al, 2010) also indicated that L1780P mutation causes adverse effects on cells in functional anlayses. Our re-classification according to the ACMG guidelines for L1780P variant published in Cancer Research and Treatment (Park et al, 2017, e-pub).
Breast Center,Key Laboratory of Carcinogenesis and Translational Research RCV000048948 SCV001430320 pathogenic Hereditary breast and ovarian cancer syndrome 2020-05-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112624 SCV000145469 uncertain significance Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112624 SCV001242658 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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