Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000048948 | SCV000076961 | pathogenic | Hereditary breast ovarian cancer syndrome | 2023-04-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 10811118, 20378548, 20516115, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 55541). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 15117986, 17100994, 22217648, 27124784, 27383479, 27488874, 27658390, 28111427, 28288110, 28364669, 29020732, 29770616). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80357474, gnomAD 0.006%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1780 of the BRCA1 protein (p.Leu1780Pro). |
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. |
Gene |
RCV000236823 | SCV000293458 | likely pathogenic | not provided | 2020-06-30 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: absent or reduced protease sensitivity, binding activity and specificity, cell survival, and transcription activity (Hayes 2000, Lee 2010, Findlay 2018); Observed in multiple individuals of Korean ancestry with breast and/or ovarian cancer (Choi 2004, Han 2006, Jang 2012, Eoh 2016, Yoon 2016, Ryu 2017); Case control studies in Korean women suggest this variant is associated with hereditary breast and ovarian cancer and may be a pathogenic Korean founder variant (Park 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5458T>C; This variant is associated with the following publications: (PMID: 20378548, 19491284, 15235020, 27124784, 29240602, 27383479, 30415210, 20516115, 15117986, 17100994, 16949048, 22217648, 15172985, 10811118, 28111427, 28781887, 29020732, 28364669, 27658390, 28288110, 27488874, 29770616, 30209399, 30765603, 30309222, 32019279, 30350268) |
Center for Breast Cancer, |
RCV000048948 | SCV000484656 | pathogenic | Hereditary breast 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, |
RCV000112624 | SCV000512304 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 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, |
RCV000048948 | SCV001430320 | pathogenic | Hereditary breast ovarian cancer syndrome | 2020-05-01 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000236823 | SCV004219456 | pathogenic | not provided | 2023-02-02 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.000008 (2/251430 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as a founder mutation in the Korean population (PMIDs: 28111427 (2017), 28364669 (2017), 30309222 (2019)). It has been found in individuals with breast and/or ovarian cancer (PMIDs: 115117986 (2004), 17100994 (2006), 22217648 (2012), 27124784 (2016), 27488874 (2017), 27658390 (2017), 28364669 (2017), 28111427 (2017), 29020732 (2018), 29240602 (2018), 30309222 (2019), 30350268 (2019), 32019279 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1), and 34645131 (2022)). Additionally, the variant has been reported in healthy individuals (PMIDs: 17100994 (2006), 22217648 (2012), and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)). Functional studies describe the variant as having a strong impact on the BRCA1 gene that results in the loss of protein function (PMIDs: 20516115 (2010), 30209399 (2018), 30415210 (2018), 30765603 (2019), 31907386 (2020), 32803532 (2020), 32546644 (2020), and 33087888 (2021)). Based on the available information, this variant is classified as pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000048948 | SCV004803448 | pathogenic | Hereditary breast ovarian cancer syndrome | 2024-01-02 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.5339T>C (p.Leu1780Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251430 control chromosomes. c.5339T>C has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and showed damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Breast Cancer Information Core |
RCV000112624 | SCV000145469 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2002-06-20 | no assertion criteria provided | clinical testing | |
Brotman Baty Institute, |
RCV000112624 | SCV001242658 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro | ||
BRCAlab, |
RCV000112624 | SCV004243918 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2020-03-02 | no assertion criteria provided | clinical testing |