ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.367C>G (p.His123Asp) (rs786204931)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000693998 SCV001244237 pathogenic PTEN hamartoma tumor syndrome 2019-11-22 reviewed by expert panel curation PTEN c.367C>G (p.His123Asp) meets criteria to be classified as pathogenic 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). PS3: Phosphatase activity <50% of wild type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 29706350, 21828076) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM2: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000580072.3)
Ambry Genetics RCV000491887 SCV000580072 likely pathogenic Hereditary cancer-predisposing syndrome 2016-09-14 criteria provided, single submitter clinical testing The p.H123D variant (also known as c.367C>G), located in coding exon 5 of the PTEN gene, results from a C to G substitution at nucleotide position 367. The histidine at codon 123 is replaced by aspartic acid, an amino acid with similar properties. This alteration was previously detected in a 53-year-old female with a clinical diagnosis of Cowden syndrome (Bussaglia E et al. J. Invest. Dermatol., 2002 Apr;118:639-44). This alteration occurs in the PTEN phosphatase signature motif and in vivo functional studies performed in yeast demonstrated loss of intrinsic catalytic activity (Rodr&iacute;guez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000693998 SCV000822422 likely pathogenic PTEN hamartoma tumor syndrome 2018-07-18 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 123 of the PTEN protein (p.His123Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Cowden syndrome (CS) associated tumors in a family (Invitae), and reported in an individual affected with CS (PMID: 11918710). ClinVar contains an entry for this variant (Variation ID: 428277). This variant falls in the conserved P-loop in the active site of the PTEN protein (PMID: 10555148). Experimental studies have shown that this missense change fully abrogated the PIP3 phosphatase activity of PTEN in a yeast assay (PMID: 21828076). Variants that disrupt the p.His123 amino acid residue in PTEN have been observed in affected individuals (PMID: 21828076, 10555148, 16619501, 10772829, 9256433, 9259288, 21291452, Invitae). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV001332360 SCV001524662 pathogenic Cowden syndrome 1 2020-07-27 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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