ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2180C>T (p.Pro727Leu) (rs80356912)

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Total submissions: 9
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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) RCV000077509 SCV001161493 benign 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 1 based on posterior probability = 0.000167
Ambry Genetics RCV000215724 SCV000275645 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-25 criteria provided, single submitter clinical testing The p.P727L variant (also known as c.2180C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2180. The proline at codon 727 is replaced by leucine, an amino acid with similar properties. This alteration was detected in an individual with a personal and family history of pancreatic cancer and in an Italian patient who underwent BRCA1/2 gene sequencing (Ghiorzo P et al. J. Med. Genet. 2012 Mar;49(3):164-70; Zanella I et al. Exp Mol Pathol. 2017 Apr;102(2):314-320). Analysis of conservation in multiple mammalian species indicates that this position is not fixed and is, therefore, less likely to be functionally important (Burk-Herrick A et al. Mamm. Genome 2006 Mar;17(3):257-70). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000350348 SCV000329125 uncertain significance not provided 2016-06-03 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2180C>T at the cDNA level, p.Pro727Leu (P727L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). Using alternate nomenclature, this variant would be defined as BRCA1 2299C>T. This variant has been observed in at least one individual with a personal and family history of pancreatic cancer (Ghiorzo 2012). BRCA1 Pro727Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Pro727Leu occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Pro727Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000215724 SCV000912042 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 727 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with pancreatic cancer (PMID: 22368299) and breast cancer (PMID: 26727311) . This variant has been identified in 3/250472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000350348 SCV001133516 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174871 SCV001338266 uncertain significance not specified 2020-02-14 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2180C>T (p.Pro727Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. In addition, at least two papers report that this variant was classified as non-pathogenic based on segregation analysis alone or multifactorial likelihood analysis incorporating segregation, pathology, and other data points (Flower_2015, Padilla_2019). The variant allele was found at a frequency of 1.2e-05 in 250472 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2180C>T has been reported in the literature in individuals affected with breast cancer, ovarian cancer and pancreatic cancer (Shattuck-Eidens_1997, Gorringe_2008, Ghiorzo_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001323203 SCV001514109 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 727 of the BRCA1 protein (p.Pro727Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs80356912, ExAC 0.003%). This variant has been reported in a family affected with pancreatic cancer or breast cancer (PMID: 22368299, 9333265) and also in an individual affected with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 54486). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 31131967). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000077509 SCV000109309 uncertain significance Breast-ovarian cancer, familial 1 2011-02-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077509 SCV000144320 uncertain significance Breast-ovarian cancer, familial 1 1997-11-14 no assertion criteria provided clinical testing

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