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

dbSNP: rs587780544

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000588392	SCV000222138	benign	not provided	2018-02-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21659347, 22995991, 11156385, 16287957, 28677221, 11120338)
Invitae	RCV000203983	SCV000262183	benign	PTEN hamartoma tumor syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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	likely benign	not provided	2023-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254681	SCV000696532	benign	not specified	2022-06-21	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.210-7_210-3delCTTTT deletes 5 nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One publication reports experimental evidence that this variant affects mRNA splicing (Huang_2000), however, this effect was not confirmed in three other experimental studies (Brown_2000, Chen_2017, Casadei_2019), suggesting the variant does not significantly impact mRNA splicing. The variant allele was found at a frequency of 0.00029 in 249498 control chromosomes (gnomAD). 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 (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. Fourteen ClinVar submitters, including one expert panel (ClinGen PTEN Variant Curation Expert Panel), have assessed the variant since 2014: one classified the variant as pathogenic, five as VUS, five as likely benign, and three (including the expert panel) as benign. Based on the evidence outlined above, the variant was classified as benign.
Eurofins Ntd Llc (ga)	RCV000254681	SCV000709617	likely benign	not specified	2017-06-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798452	SCV002042718	likely benign	Breast and/or ovarian cancer	2023-03-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131492	SCV002528224	benign	Hereditary cancer-predisposing syndrome	2020-10-29	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254681	SCV002549957	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272138	SCV002556568	benign	Familial cancer of breast	2020-11-11	criteria provided, single submitter	clinical testing	The PTEN c.210-7_210-3del5 variant is classified as Benign (BS2, BP6_Strong) PTEN c.210-7_210-3del5 is located in intron 3. This variant has been observed in a healthy control population at a frequency which is inconsistent with expectations given the high penetrance of this condition under curation (BS2).
CeGaT Center for Human Genetics Tuebingen	RCV000588392	SCV004009999	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PTEN: BP4
Myriad Genetics, Inc.	RCV000409649	SCV004019894	likely benign	Cowden syndrome 1	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003945148	SCV004774489	likely benign	PTEN-related condition	2023-10-04	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.
Clinical Genetics, Academic Medical Center	RCV000254681	SCV001925269	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588392	SCV001967747	likely benign	not provided		no assertion criteria provided	clinical testing