ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3649T>C (p.Ser1217Pro) (rs273900712)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048271 SCV000076284 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 1217 of the BRCA1 protein (p.Ser1217Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs273900712, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with breast and/or ovarian cancer, and pancreatic cancer (PMID: 19016756, 21232165, 27062684, 19029836, 25356972, 28993434, 30287823). This variant is also known as 3768T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 54953). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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.
Ambry Genetics RCV000164401 SCV000215037 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000758816 SCV000292516 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3649T>C at the cDNA level, p.Ser1217Pro (S1217P) at the protein level, and results in the change of a Serine to a Proline (TCT>CCT). Also reported as BRCA1 3768T>C using alternate nomenclature, this variant has been observed in individuals with breast, ovarian, and/or pancreatic cancer (Sugano 2008, Axilbund 2009, Stegel 2011, Zhen 2015, Azzollini 2016, Wen 2018). This variant has been reported to abolish local CK2A1 and CSNK2A1 binding, preventing phosphorylation of this residue in in vivo studies; however the biological significance of this is not known (Tram 2013). BRCA1 Ser1217Pro was observed at an allele frequency of 0.05% (12/25,792) in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Ser1217Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000112145 SCV000488309 uncertain significance Breast-ovarian cancer, familial 1 2016-02-19 criteria provided, single submitter clinical testing
Color RCV000164401 SCV000683120 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758816 SCV000887673 uncertain significance not provided 2019-05-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765362 SCV000896627 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194349 SCV001363819 uncertain significance not specified 2019-01-09 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3649T>C (p.Ser1217Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 282742 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (9.2e-05 vs 0.001), allowing no conclusion about variant significance. c.3649T>C has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (Sugano 2008, Stegel 2011, Azzollini 2016, Wen 2017) and pancreatic cancer (Axilbund 2009, Zhen 2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication reported that the variant abolishes a potential phosphorylation site, however it does not allow convincing conclusions about the variant effect (Tram 2013). As-least one unpublished co-occurrence in patients from families with putative pathogenic variants in BRCA2 (reported as BRCA2 1466delT and 429 Stop, Adami et al, 2010) has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112145 SCV000144823 uncertain significance Breast-ovarian cancer, familial 1 2010-12-17 no assertion criteria provided clinical testing

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