Submissions for variant NM_000314.8(PTEN):c.91A>G (p.Asn31Asp)

dbSNP: rs1859093459

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV001213866	SCV004183303	likely pathogenic	PTEN hamartoma tumor syndrome	2023-08-04	reviewed by expert panel	curation	NM_000314.8(PTEN):c.91A>G (p.Asn31Asp) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. [internal laboratory contributor(s)] PS4_P: Proband(s) with phenotype specificity score of 1-1.5. [internal laboratory contributor(s)] PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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. PP3: in silico REVEL score of 0.966 (>0.7) BS3_P: Well-established functional studies show no deleterious effect: Phosphatase activity >0 (score = 0.549559228) per Mighell et al. 2018 (PMID: 29706350). Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 pathogenic strong, 4 pathogenic supporting and 1 benign supporting codes get (4*1) + (1*4)+ (- 1*1) points = total is 7 (Likely Pathogenic).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001213866	SCV001385518	uncertain significance	PTEN hamartoma tumor syndrome	2021-08-15	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PTEN-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 31 of the PTEN protein (p.Asn31Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid.
GeneDx	RCV001570987	SCV001795371	pathogenic	not provided	2020-06-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29706350)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001213866	SCV005400410	likely pathogenic	PTEN hamartoma tumor syndrome	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with PTEN-related disease (OMIM). Loss of function is the mechanism for null variants while missense variants have been demonstrated to exert either a loss of function or dominant-negative mechanism (PMID: 20301661). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In particular, PTEN-related Proteus syndrome has been described to be a highly variable disorder (PMID: 20301661). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change, p.(Asn31Lys), has been reported as a VUS by a clinical laboratory in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as likely pathogenic by an expert panel in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign