ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.210-7_210-3del (rs587780544)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000203983 SCV000930129 benign PTEN hamartoma tumor syndrome 2019-03-05 reviewed by expert panel curation PTEN c.210-7_210-3delCTTTT (IVS3-7_IVS3-3delCTTTT) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). BS1: Allele frequency of 0.00136 (0.14%, 14/10,306 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221)
Ambry Genetics RCV000131492 SCV000186480 likely benign Hereditary cancer-predisposing syndrome 2018-11-20 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
GeneDx RCV000254681 SCV000222138 likely benign not specified 2017-06-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000203983 SCV000262183 benign PTEN hamartoma tumor syndrome 2020-12-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000203983 SCV000365737 uncertain significance PTEN hamartoma tumor syndrome 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000409649 SCV000487849 uncertain significance Cowden syndrome 1 2015-11-23 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000254681 SCV000596623 uncertain significance not specified 2016-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588392 SCV000602118 uncertain significance not provided 2020-05-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254681 SCV000696532 likely benign not specified 2021-06-14 criteria provided, single submitter clinical testing Variant summary: PTEN c.210-7_210-3delCTTTT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: one predict the variant abolishes a 3 prime acceptor site; three predict the variant weakens a 3 prime acceptor site. One publication reports experimental evidence that this variant affects mRNA splicing (Huang_2000), however, this effect was not found in the other three experimental studies (Brown_2000, Chen_2017, Casadei_2019). The variant allele was found at a frequency of 0.00029 in 249498 control chromosomes. The observed variant frequency is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (1.6e-05), strongly suggesting that the variant is benign. c.210-7_210-3delCTTTT has been reported in the literature in individuals affected with different types of cancer without unequivocal conclusion. Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=7, VUS n=5, pathogenic n=1). Based on the evidence outlined above, the variant was classified as likely benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000254681 SCV000709617 likely benign not specified 2017-06-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131492 SCV000902621 likely benign Hereditary cancer-predisposing syndrome 2015-11-13 criteria provided, single submitter clinical testing
Mendelics RCV000203983 SCV001138126 likely benign PTEN hamartoma tumor syndrome 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomic Medicine Translational Research Lab,Cleveland Clinic Genomic Medicine Institute RCV000409649 SCV000579248 uncertain significance Cowden syndrome 1 2017-05-26 no assertion criteria provided research
King Laboratory,University of Washington RCV000203983 SCV001251381 pathogenic PTEN hamartoma tumor syndrome 2019-09-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000588392 SCV001554034 uncertain significance not provided no assertion criteria provided clinical testing The PTEN c.210-7_210-3del variant was identified in 18 of 5644 proband chromosomes (frequency: 0.003) from individuals or families with endometrial cancer, Cowden syndrome, Li Fraumeni, and breast cancer (Black 2004, Brown 2000, Chen 2017 , Hobert 2012, Pilarski 2011, Sweet 2005, Tung 2015). The variant was also identified in dbSNP (ID: rs587780544) as “With other allele”, in ClinVar (with conflicting interpretations of pathogenicity; as likely benign by GeneDx, Invitae, and Integrated Genetics, and as uncertain significance by Ambry, Illumina, Counsyl, University of Chicago, Quest Diagnostics, EGL Genetic Diagnostics, and Cleveland Clinic), Cosmic (in endometrioid carcinoma), LOVD 3.0, and in the Zhejiang University Database (in individuals with Familial Juvenile Polyposis). The variant was not identified in the MutDB database. The variant was identified in control databases in 78 of 275204 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Ashkenazi Jewish in 16 of 10086 chromosomes (freq: 0.002), Other in 4 of 6406 chromosomes (freq: 0.0006), European (Non-Finnish) in 38 of 125410 chromosomes (freq: 0.0003), African in 7 of 23920 chromosomes (freq: 0.0003), Latino in 9 of 34240 chromosomes (freq: 0.0003), East Asian in 3 of 18782 chromosomes (freq: 0.0002), and South Asian in 1 of 30656 chromosomes (freq: 0.00003), while the variant was not observed in the Finnish population. The c.210-7_210-3del variant has inconsistent predictions of pathogenicity in the literature. Two functional studies of patients with Li-Fraumeni and Cowden syndrome showed the variant had no deleterious effect on mRNA processing (Brown 2000, Chen 2017). However, another study found an individual with the variant who met full Cowden syndrome diagnostic criteria exhibited elevated succinate in both plasma and urine, and concluded that the variant may actually be pathogenic (Hobert 2012). Another study of a family in which an unaffected father carried the variant, and his twin daughters both carried the variant and were affected with Juvenile Polyposis, concluded that RT-PCR analysis demonstrated the variant appears to affect RNA splicing (Huang 2000). The c.210-7_210-3del variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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