Submissions for variant NM_000314.6(PTEN):c.-975G>A

dbSNP: rs587780001

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV001078168	SCV001244239	likely benign	PTEN hamartoma tumor syndrome	2019-11-22	reviewed by expert panel	curation	PTEN c.-975G>A (NC_000010.10:g.89623251G>A) meets criteria to be classified as likely benign 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). BS1: Allele frequency of 0.00127 (0.127%, 11/8660 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (internal laboratory contributor ClinVar Organization ID: 61756)
GeneDx	RCV000587663	SCV000149488	benign	not provided	2017-12-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25669429)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587663	SCV000696554	benign	not provided	2017-05-15	criteria provided, single submitter	clinical testing	Variant summary: The PTEN c.-975G>A (also known as c.-976G>A) variant involves the alteration of a non-conserved nucleotide located in the promoter region of PTEN. One in silico tool predicts a benign outcome for this variant. This variant was found in 20/30846 control chromosomes (gnomAD) at a frequency of 0.0006484, which is approximately 104 times the estimated maximal expected allele frequency of a pathogenic PTEN variant (0.0000063), suggesting this variant is likely a benign polymorphism. A publication, Nizialek_2015, cites the variant to have been found in their cohort, however, it is unclear as to whether the variant was found in affected individuals or controls. Although the authors do report another variant at this position, c.-976G>C that segregated with CS in the family and was observed to have promoter methylation, although methylation is commonly associated with C residues. A clinical diagnostic laboratory cites the variant as "uncertain significance." In addition, an internal LCA sample reports the variant to co-occur with a likely pathogenic TP53 variant, c.375+2T>C. Therefore, the variant of interest has been classified as Benign.
Genetic Services Laboratory, University of Chicago	RCV001818272	SCV002071955	uncertain significance	not specified	2019-04-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256044	SCV002528279	benign	Hereditary cancer-predisposing syndrome	2020-09-29	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000587663	SCV004009995	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PTEN: BS1
Breakthrough Genomics, Breakthrough Genomics	RCV000587663	SCV005221857	likely benign	not provided		criteria provided, single submitter	not provided