ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5339T>C (p.Leu1780Pro) (rs80357474)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132201 SCV000187283 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Breast Cancer Information Core (BIC) (BRCA1) RCV000112624 SCV000145469 uncertain significance Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing
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).
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.
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.
Invitae RCV000048948 SCV000076961 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-11 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 (rs80357474, ExAC no frequency). This variant has been reported in several individuals and families affected with hereditary breast and ovarian cancer (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). Experimental studies have shown that this missense change has a severe effect on BRCA1 protein folding, binding ability, and transcriptional activation (PMID: 10811118, 20516115, 20378548). In summary, this variant has been reported in both affected and unaffected individuals and has been shown to compromise protein function. In the absence of further supportive evidence this variant has been classified as a Variant of Uncertain Significance.

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