ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.579G>A (p.Leu193=)

gnomAD frequency: 0.00003  dbSNP: rs568851024
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000123049 SCV001244238 likely benign PTEN hamartoma tumor syndrome 2019-11-22 reviewed by expert panel curation PTEN c.579G>A (p.Leu193=) meets criteria to be classified as likely 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 0.00125 (0.125%, 13/10,360 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.
Invitae RCV000123049 SCV000166344 benign PTEN hamartoma tumor syndrome 2021-12-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162705 SCV000213165 likely benign Hereditary cancer-predisposing syndrome 2014-09-18 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.
Illumina Laboratory Services,Illumina RCV000123049 SCV000365739 benign PTEN hamartoma tumor syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx RCV000437368 SCV000514312 benign not specified 2015-06-26 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.
Genetic Services Laboratory,University of Chicago RCV000437368 SCV000596621 likely benign not specified 2016-07-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000162705 SCV000686293 likely benign Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000437368 SCV000696536 benign not specified 2019-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000663101 SCV000786211 likely benign Cowden syndrome 1 2018-03-22 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001312160 SCV001502625 likely benign not provided 2020-09-01 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000162705 SCV002528249 likely benign Hereditary cancer-predisposing syndrome 2021-07-12 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357128 SCV001552488 benign Malignant tumor of breast no assertion criteria provided clinical testing The PTEN p.Leu193= variant was identified in 2 of 2194 proband chromosomes (frequency: 0.001) from individuals or families with Cowden syndrome (Nizialek 2015, Sarquis 2006). The variant was also identified in dbSNP (ID: rs568851024) as With other allele, ClinVar (classified as benign by Invitae, GeneDx; as likely benign by Ambry Genetics, Color Genomics; as uncertain significance by Integrated Genetics), Clinvitae, LOVD 3.0, databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 27 of 276780 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 2 of 6458 chromosomes (freq: 0.0003), Latino in 5 of 34416 chromosomes (freq: 0.0002), European in 5 of 126450 chromosomes (freq: 0.00004), Ashkenazi Jewish in 13 of 10142 chromosomes (freq: 0.001), and South Asian in 2 of 30762 chromosomes (freq: 0.0001), while the variant was not observed in the African, East Asian, Finnish, populations. The p.Leu193= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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