ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1A>G (p.Met1Val) (rs1554890324)

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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 RCV000706088 SCV001244242 pathogenic PTEN hamartoma tumor syndrome 2019-11-22 reviewed by expert panel curation PTEN c.1A>G (p.M1?) 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). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5' to c.1121 (NM_000314.4). PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 29752200) PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 29752200, 28774669; internal laboratory contributor ClinVar Organization ID: 26957)
Ambry Genetics RCV000572416 SCV000671706 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-08 criteria provided, single submitter clinical testing The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the PTEN gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine 35 amino acids from the initiation site. An alternate variant at the initiation codon, c.1A>C (p.M1L), was identified in a high-risk breast and/or ovarian cancer patient from Hong Kong and was considered pathogenic (Kwong A et al. J Mol Diagn, 2016 Jul;18:580-94). Also, another alteration, c.3G>T (p.M1I), was reported in an 11 year old male who had a clinical diagnosis of autism spectrum disorder, macrocephaly, café-au-lait macules, seizure history, oral mucosal papillomatosis, and penile freckling. His 12 year old brother also tested positive for this alteration and he had a clinical diagnosis of ASD as well as macrocephaly, oral mucosal papillomatosis, penile freckling, and seizure history (Hobert JA et al. Eur. J. Hum. Genet., 2014 Feb;22:273-6). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000706088 SCV000835120 likely pathogenic PTEN hamartoma tumor syndrome 2019-09-09 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the PTEN mRNA. The next in-frame methionine is located at codon 35. This variant is not present in population databases (ExAC no frequency). Disruption of the Met1 initiator codon has been observed in the literature in individuals affected with PTEN-related disease (PMID: 28774669, 29752200, 27157322, 28600779, 23695273). ClinVar contains an entry for this variant (Variation ID: 484600). A missense variant (p.Asp24Gly) located upstream of the next in-frame methionine has been determined to be pathogenic (PMID: 21194675, 22503188, 24498881, Invitae). This indicates that the N-terminal region is critical for PTEN protein function. 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.
GeneDx RCV001562180 SCV001784907 pathogenic not provided 2019-07-29 criteria provided, single submitter clinical testing Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29752200, 28774669, 27157322, 25669429, 23695273)

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