ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5165C>T (p.Ser1722Phe) (rs80357104)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048839 SCV000076852 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-21 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 individuals affected with breast cancer and/or ovarian cancer (PMID: 22476429, 30093976). 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.
Ambry Genetics RCV000214443 SCV000273727 pathogenic Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing The p.S1722F pathogenic mutation (also known as c.5165C>T), located in coding exon 17 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5165. The serine at codon 1722 is replaced by phenylalanine, an amino acid with highly dissimilar properties. Based on multiple structural and functional analyses, this alteration was shown to significantly alter protease sensitivity, peptide binding activity, peptide binding specificity, and transcriptional activity of the mutant protein compared to wild type (Mirkovic N et al. Cancer Res. 2004 Jun;64:3790-7; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90). This alteration has also been predicted to be deleterious based on a multifactorial likelihood-ratio model (Karchin R et al PLoS Comput. Biol. 2007 Feb;3:e26). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000236284 SCV000293277 likely pathogenic not provided 2021-03-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with respect to: protein folding, phosphopeptide binding activity and specificity, transcriptional activity, and cell viability (Carvhalo 2002, Lee 2010, Findlay 2018, Fernandes 2019); Observed in individuals with BRCA1-related cancers (Lu 2012, Chan 2018, Mersch 2018); Not observed 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 BRCA1 5284C>T; This variant is associated with the following publications: (PMID: 15172985, 30209399, 16267036, 20516115, 25085752, 12496477, 17305420, 22476429, 28781887, 15385441, 29446198, 23704879, 30264118, 30093976, 30765603, 31447099, 33087888)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236284 SCV000296373 likely pathogenic not provided 2020-03-19 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
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
Color Health, Inc RCV000214443 SCV000683267 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-22 criteria provided, single submitter clinical testing This missense variant replaces serine with phenylalanine at codon 1722 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant resulted in disruption of transcriptional activity in yeast and mammalian cell studies (PMID: 12496477, 15172985, 20516115). This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 22476429). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048839 SCV000699216 likely pathogenic Hereditary breast and ovarian cancer syndrome 2021-05-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5165C>T (p.Ser1722Phe) results in a non-conservative amino acid change located in the first BRCT domain (IPR001357) that binds ATM-phosphorylated proteins (e.g. abraxas, CtIP and BRIP1; see PMID 22193408). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251036 control chromosomes (gnomAD). c.5165C>T has been reported in the literature in individuals with personal and/or family history of breast- and ovarian cancer (Judkins_2005, Lu_2012, Chan_2018, Lynce_2020). Publications also reported experimental evidence, demonstrating decreased structural stability, impaired phosphopeptide binding and transcriptional activity (Lee_2010); and in a recent high throughput genome editing assay the variant resulted in a decreased (intermediate) function when testing it in a haploid human cell line whose survival is dependent on intact BRCA1 function (Findlay_2018). Ten other 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 pathogenic (n=2) or likely pathogenic (n=8). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mendelics RCV000048839 SCV000839214 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
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.
Mendelics RCV000077606 SCV001140481 likely pathogenic Breast-ovarian cancer, familial 1 2019-05-28 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
Breast Cancer Information Core (BIC) (BRCA1) RCV000077606 SCV000145368 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354040 SCV000591589 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Ser1722Ph variant falls within the BRCA1 C-terminus (BRCT) domain and was shown, in a yeast based transcription activation assay, to be temperature sensitive whereby activity was abolished at 37oC, and therefore likely represents a cancer-associated variant (Carvalho 2002). Lee et al (2010) used 3 biochemical and cell-based transcriptional assays to show that the variant had a strong functional effect and is likely associated with increased cancer risk. Other functional/computational models validated by such biochemical assays have also shown the variant to be deleterious (Mirkovic 2004, Karchin 2007). The variant was also identified in dbSNP (ID: rs80357104) “With other allele”, but no frequency information was provided, the variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) or the 1000 Genomes Browser. The variant was present in the Clinvitae database, the ClinVar database (with conflicting interpretations of pathogenicity: classified as pathogenic by Sharing Clinical Reports Project derived from Myriad reports; uncertain significance by BIC, and classification not provided by Invitae), Fanconi Anemia Mutation Database (LOVD), COSMIC (1x in a cervical tissue/squamous cell carcinoma), the BIC database (2X with unknown clinical importance), and UMD (1X with a 3-UV ”unclassified variant”). The p.Ser1722 residue is conserved across mammals and most other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as likely pathogenic.
Brotman Baty Institute,University of Washington RCV000077606 SCV001237797 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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