ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5165C>T (p.Ser1722Phe) (rs80357104)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214443 SCV000273727 pathogenic Hereditary cancer-predisposing syndrome 2017-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA1) RCV000077606 SCV000145368 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Color RCV000214443 SCV000683267 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077606 SCV000326192 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077606 SCV000677659 likely pathogenic Breast-ovarian cancer, familial 1 2017-04-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048839 SCV000591589 likely pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
GeneDx RCV000236284 SCV000293277 likely pathogenic not provided 2018-02-27 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5165C>T at the cDNA level, p.Ser1722Phe (S1722F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). Using alternate nomenclature, this variant would be defined as BRCA1 5284C>T. This variant has been observed in at least one individual with breast cancer (Lu 2012). In functional studies, BRCA1 Ser1722Phe was shown to severely impact protein folding, phosphopeptide binding activity and specificity, and transcriptional activity (Carvhalo 2002, Lee 2010). BRCA1 Ser1722Phe was not observed in large population cohorts (Lek 2016). This variant is located in the BRCT1 domain, the DNA binding domain, and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider BRCA1 Ser1722Phe to be a likely pathogenic variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000077606 SCV000839899 likely pathogenic Breast-ovarian cancer, familial 1 2017-05-25 criteria provided, single submitter clinical testing The c.5165C>T (p.Ser1722Phe) variant in the BRCA1 gene has been reported in two patients in the Breast Cancer Information Core database (accession number 10462 and 10461). The variant has also been reported in additional patients by clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55441). Functional assays showed a strong deleterious effect [PMID 20516115]. This variant was not observed in the ExAC database. Serine at amino acid position 1722 of the BRCA1 protein is conserved in mammals. Although not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Ser1722Phe change to be deleterious. This variant thus classified as likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000048839 SCV000699216 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-09-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5165C>T (p.Ser1722Phe) variant involves the alteration of a conserved nucleotide. The variant is located in BCRT domain of the protein (InterPro) and within 10 nucleotides of a phosphorylation site (Thr1720) (Tram_2013). 4/5 in silico tools predict a damaging outcome for this variant. This variant was absent in approximately 120062 control chromosomes from ExAC. Validated functional studies show severe impairment of transcriptional activity and binding to pSer-X-X-Phe motif, a known functional target of the BRCA1 BRCT domain (Lee_2010). The variant has been reported in multiple HBOC patients/families or individuals undergoing BRCA1/2 testing in literature and clinical databases (UMD, BIC, Judkins_2005, and Lu_2012). There were no published co-segregation studies for the variant at the time of variant classification. The variant has been classified as an uncertain significance in the literature (Judkins_2005 and Lu_2012) and clinical databases (UMD and BIC). However five diagnostic centers have classified the variant as likely pathogenic/pathogenic in ClinVar. Another missense change at the same residue, p.Ser1722Pro, has also been reported in HBOC patients and was classified as likely pathogenic by a lab in ClinVar. This variant can be considered to meet ACMG PS3, PM1, PM2 and PP3 rules. Taken together, this variant is currently classified as Likely Pathogenic.
Invitae RCV000048839 SCV000076852 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-24 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 1722 of the BRCA1 protein (p.Ser1722Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 22476429). ClinVar contains an entry for this variant (Variation ID: 55441). Experimental studies have shown that this missense change disrupts the protein folding, peptide binding activity and specificity, and transcriptional activation activity of the BRCA1 protein (PMID: 20516115, 12496477). Using a multifactorial likelihood algorithm based on weighting individual's personal and family history of cancer, this variant has been determined to have a high probability of being pathogenic (PMID: 25085752). In summary, this is a rare missense variant shown to disrupt protein function in vitro and has been predicted to be deleterious based on gene-specific and multifactorial likelihood analyses. It is absent from the population and reported in affected individuals, however, without additional genetic data, this variant has been classified as Likely Pathogenic.
Mendelics RCV000048839 SCV000839214 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236284 SCV000296373 likely pathogenic not provided 2017-11-19 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077606 SCV000109409 pathogenic Breast-ovarian cancer, familial 1 2012-08-17 no assertion criteria provided clinical testing

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