ClinVar Miner

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

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491887 SCV000580072 likely pathogenic Hereditary cancer-predisposing syndrome 2016-09-14 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
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.

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