ClinVar Miner

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

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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 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 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.
Invitae RCV000232250 SCV000284582 benign PTEN hamartoma tumor syndrome 2020-11-25 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 Health, Inc 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358042 SCV001553681 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The PTEN p.Asp368= variant was identified in 2 of 2104 proband chromosomes (frequency: 0.001) from individuals or families with prostate cancer or Cowden syndrome (Nizialek 2015, Dong 1998). The variant was also identified in dbSNP (ID: rs35979531) as "With Uncertain significance, other allele", ClinVar (classified as benign by GeneDx, Invitae and two other submitters; and as likely benign by Ambry Genetics, Color Genomics and one other submitter), and LOVD 3.0 (2x). The variant was not identified in the Cosmic or Zhejiang University databases. The variant was identified in 151 of 265518 chromosomes at a frequency of 0.0006, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 130 of 22966 chromosomes (freq: 0.006), Other in 2 of 6210 chromosomes (freq: 0.0003), Latino in 12 of 33662 chromosomes (freq: 0.0004), European in 2 of 119394 chromosomes (freq: 0.00002), and South Asian in 5 of 29884 chromosomes (freq: 0.0002); it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asp368= 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) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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