ClinVar Miner

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

gnomAD frequency: 0.00008  dbSNP: rs273900712
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048271 SCV000076284 likely benign Hereditary breast ovarian cancer syndrome 2024-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000164401 SCV000215037 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-21 criteria provided, single submitter clinical testing The p.S1217P variant (also known as c.3649T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 3649. The serine at codon 1217 is replaced by proline, an amino acid with similar properties. This variant has been reported in both controls and cases from several cancer cohorts, including breast, ovarian, and pancreatic cancer cohorts (Sugano K et al, Cancer Sci. 2008 Oct; 99(10):1967-76; Stegel V et al, BMC Med. Genet. 2011; 12:9; Axilbund JE et al, Cancer Biol. Ther. 2009 Jan; 8(2):131-5; Zhen DB et al. Genet Med, 2015 Jul;17:569-77; Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Momozawa Y et al. Nat Commun. 2018 10;9(1):4083; Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was also identified in an individual diagnosed with an adrenal cortical carcinoma (Owen DH et al. Horm Cancer, 2019 Dec;10:161-167). This alteration, which changes a predicted consensus phosphorylation motif, abolished the ability of BRCA1 to bind CK2/CSNK2A1; however, the clinical significance of this deficit is unknown (Tram E, PLoS ONE 2013 ; 8(5):e62468). Of note, this alteration is also designated as 3768T>C in published literature. This amino acid position is well 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 RCV000758816 SCV000292516 uncertain significance not provided 2023-01-10 criteria provided, single submitter clinical testing Observed in individuals with breast, ovarian, and/or pancreatic cancer (Sugano et al., 2008; Axilbund et al., 2009; Stegel et al., 2011; Zhen et al., 2015; Azzollini et al., 2016; Wen et al., 2018; Kadri et al., 2020; Andrikopoulou et al., 2022; Zografos et al., 2022); Published functional studies demonstrate abolishment of local CK2A1 and CSNK2A1 binding, preventing phosphorylation of this residue in in vivo studies; however the biological significance of this is not known (Tram et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3768T>C; This variant is associated with the following publications: (PMID: 19016756, 21232165, 19029836, 27062684, 28993434, 25356972, 30287823, 30093976, 32467295, 35127508, 32068069, 33552952, 23704879, 36011273)
Counsyl RCV000112145 SCV000488309 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2016-02-19 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000164401 SCV000683120 likely benign Hereditary cancer-predisposing syndrome 2021-10-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758816 SCV000887673 uncertain significance not provided 2020-08-25 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000765362 SCV000896627 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194349 SCV001363819 uncertain significance not specified 2023-04-06 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 7.9e-05 in 327244 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (7.9e-05 vs 0.001), allowing no conclusion about variant significance. c.3649T>C has been reported in the literature in individuals affected with Breast or Ovarian Cancer without strong evidence of causality (e.g. Adami_2010, Sugano_2008, Stegel_2011, Azzollini_2016, Wen_2017, Dorling_2021, Momozawa_2018, Kadri_2021, Kwong_2020, Andrikopoulou_2021, Su_2021, Zhang_2022, Zografos_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
MGZ Medical Genetics Center RCV002250537 SCV002579372 likely benign Familial cancer of breast 2024-02-09 criteria provided, single submitter clinical testing ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BS1_SUP
University of Washington Department of Laboratory Medicine, University of Washington RCV000164401 SCV003846397 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Breast Cancer Information Core (BIC) (BRCA1) RCV000112145 SCV000144823 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2010-12-17 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354959 SCV001549694 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing
Center for Precision Medicine, Meizhou People's Hospital RCV002250537 SCV002520874 uncertain significance Familial cancer of breast no assertion criteria provided literature only
BRCAlab, Lund University RCV000112145 SCV004244033 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2020-03-02 no assertion criteria provided clinical testing

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