ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1104T>C (p.Asp368=) (rs35979531)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000232250 SCV000840471 likely benign PTEN hamartoma tumor syndrome 2016-09-14 reviewed by expert panel curation PTEN c.1104T>C (p.D368=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BS1: Allele frequency of 0.0057 (0.57%, 130/22,966 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact. BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted.
GeneDx RCV000153792 SCV000171227 benign not specified 2014-06-30 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153792 SCV000203370 benign not specified 2013-12-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162364 SCV000212670 likely benign Hereditary cancer-predisposing syndrome 2014-09-23 criteria provided, single submitter clinical testing
Invitae RCV000232250 SCV000284582 benign PTEN hamartoma tumor syndrome 2019-12-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000153792 SCV000303569 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000232250 SCV000365741 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.
Color RCV000162364 SCV000537476 likely benign Hereditary cancer-predisposing syndrome 2015-05-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759324 SCV000888579 benign not provided 2018-09-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000153792 SCV001156552 benign not specified 2019-02-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000153792 SCV001361386 benign not specified 2019-03-09 criteria provided, single submitter clinical testing Variant summary: PTEN c.1104T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00057 in 265518 control chromosomes, predominantly at a frequency of 0.0057 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 912 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Cowden Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant was also detected in the FLOSSIES database in 26 African American women who are cancer free and older than age 70, providing further supporting evidence for a benign role. However, these observations need to be cautiously considered due to the potential of the PTEN pseudogene being captured at this site. c.1104T>C has been reported in the literature in one Cowden Syndrome study but it was unclear if found in patients or controls (Nizialek_2015) and in one individual with prostate cancer (Dong_1998). These reports do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as likely benign (4x) and once as benign. Based on the evidence outlined above, the variant was classified as benign.

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