ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.388C>T (p.Arg130Ter) (rs121909224)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132187 SCV000187267 pathogenic Hereditary cancer-predisposing syndrome 2017-01-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other acmg-defined mutation (i.e. initiation codon or gross deletion)
GeneDx RCV000078615 SCV000222110 pathogenic not provided 2018-12-14 criteria provided, single submitter clinical testing This A>G nucleotide substitution results in the replacement of an Arginine codon (AGG) with a Glycine codon (GGG) at amino acid position 14, and is denoted c.40A>G at the cDNA level or p.R14G at the protein level. The novel R14G missense change has not been published as a germline pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, the R14G amino acid substitution has previously been reported as a somatic change in two colon tumors and one kidney tumor among other tumor types according to the Catalogue of Somatic Mutations in Cancer. The NHLBI ESP Exome Sequencing Project reports R14G was not observed in approximately 6500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The R14G variant is a non-conservative substitution as a positively-charged Arginine residue is replaced by a neutral Glycine residue at a position that is evolutionarily well-conserved. This amino acid substitution is located within the phosphatase tensin-type domain, a known functional domain. missense pathogenic variants in nearby positions have been reported in the literature, according to HGMD (K13E, R15S, D22G). Therefore, R14G is a strong candidate for a disease-causing mutation likely associated with a PTEN-related disorder; however the possibility that it is a benign variant cannot be excluded.
Invitae RCV000199099 SCV000253832 pathogenic PTEN hamartoma tumor syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg130*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121909224, ExAC 0.006%). This variant has been observed in several individuals affected with PTEN hamartoma tumor syndrome (PMID: 9259288, 21956414, 22266152, 23470840, 16773562, 24345843, 28655553). ClinVar contains an entry for this variant (Variation ID: 7819). Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000008263 SCV000489500 pathogenic Cowden syndrome 1 2016-10-13 criteria provided, single submitter clinical testing
Herman Laboratory,Nationwide Children's Hospital RCV000199099 SCV000579271 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506163 SCV000604969 pathogenic not specified 2017-02-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000199099 SCV000967757 pathogenic PTEN hamartoma tumor syndrome 2018-04-02 criteria provided, single submitter clinical testing The p.Arg130X variant in PTEN has been reported in at least 10 individuals with Cowden syndrome (a sub-type of PTEN hamartoma tumor syndrome) and segregated wit h disease in at least 5 affected relatives from 2 families (Nelen 1997, Marsh 19 98, Zori 1998, Kubo 2000, Ngeow 2011). This variant has been identified in 3/246 154 total chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.; dbSNP rs121909224) and in ClinVar (Variation ID# 7819). This nonsense variant leads to a premature termination codon at position 130, which is predicted to lead to a truncated or absent protein. Heterozygous loss of func tion of the PTEN gene is an established disease mechanism in PTEN hamartoma tumo r syndrome. In summary, this variant meets criteria to be classified as pathogen ic for PTEN hamartoma tumor syndrome in an autosomal dominant manner. ACMG/AMP C riteria applied PVS1; PS4; PP1_Moderate.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078615 SCV001134775 pathogenic not provided 2019-08-26 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
OMIM RCV000008263 SCV000028470 pathogenic Cowden syndrome 1 2007-03-15 no assertion criteria provided literature only
OMIM RCV000008265 SCV000028472 pathogenic Macrocephaly/autism syndrome 2007-03-15 no assertion criteria provided literature only
Pathway Genomics RCV000008263 SCV000189986 pathogenic Cowden syndrome 1 2014-07-24 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000443514 SCV000504380 likely pathogenic Neoplasm of brain 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424529 SCV000504381 pathogenic Ovarian Neoplasms 2014-10-02 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000078615 SCV000692010 pathogenic not provided no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000424529 SCV000923927 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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