Submissions for variant NM_006218.4(PIK3CA):c.1030G>A (p.Val344Met)

dbSNP: rs1057519942

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485942	SCV000569339	pathogenic	not provided	2024-05-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21984976, 26226847, 31278258, 26492180, 34906519, 26619011, 24573554, 22653804, 25343854, 22102435, 23907151, 27631024, 30167082, 28973083, 29296277, 31568861, 31785789, 35599849)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631216	SCV000752230	pathogenic	Cowden syndrome	2021-07-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 376498). This missense change has been observed in individual(s) with megalencephaly (PMID: 27631024; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 344 of the PIK3CA protein (p.Val344Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine.
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000767535	SCV000898153	pathogenic	Cowden syndrome 5	2018-06-25	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000767535	SCV002581519	pathogenic	Cowden syndrome 5	2022-04-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000767535	SCV003835708	pathogenic	Cowden syndrome 5	2022-11-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000485942	SCV003916859	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PIK3CA: PS2, PM2, PS4:Moderate, PP3, PP4
Illumina Laboratory Services, Illumina	RCV003985084	SCV004801565	pathogenic	PIK3CA related overgrowth syndrome	2021-05-23	criteria provided, single submitter	clinical testing	The PIK3CA c.1030G>A p.(Val344Met) variant is a missense variant that has been reported in a heterozygous state in three individuals with features of megalencephaly-capillary malformation; the variant was maternally inherited in one individual and occurred de novo in the other two cases (Mirzaa et al. 2016; Yeung et al. 2017; De Graer et al. 2020). Meng et al. (2017) also reported the variant in a heterozygous state in a critically ill infant for whom no additional phenotype details were provided. This variant is not observed in version 2.1.1 or 3.1.2 of the Genome Aggregation Database. Based on the collective evidence the c.1030G>A p.(Val344Met) variant is classified as pathogenic for PIK3CA-related overgrowth spectrum.
Ambry Genetics	RCV004955473	SCV005468931	pathogenic	Inborn genetic diseases	2024-09-26	criteria provided, single submitter	clinical testing	The c.1030G>A (p.V344M) alteration is located in exon 5 (coding exon 4) of the PIK3CA gene. This alteration results from a G to A substitution at nucleotide position 1030, causing the valine (V) at amino acid position 344 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a mosaic or heterozygous mutation, de novo when parents were tested, in multiple individuals with megalencephaly, macrocephaly, hemihypertrophy, polydactyly, autism, speech delay, and/or dysmorphic facial features (Mirzaa, 2016; De Graer, 2020; Cooley Coleman, 2023; DECIPHER). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Center of Human Genetics, Erasme Hospital	RCV000852337	SCV000920642	pathogenic	Hypertelorism; Megalencephaly, autosomal dominant; Diaphragmatic eventration; Abnormality of the hairline; Intestinal duplication	2019-06-06	no assertion criteria provided	clinical testing	The c.1030G>A p.(Val344Met) has been identified by our team in a fetus showing megalencephaly, left diaphragmatic eventration, facial dysmorphism (hypertelorism, abnormal hair line implantation) and duplication of distal portion of the small bowel. The variant arose as a de novo event and it was present in several fetal tissues. In addition, the c.1030G>A p.(Val344Met) variant has been previously reported at de novo constitutional state in two patients presenting megalencephaly (Mirzaa et al., 2016; Yeung et al., 2017). Moreover, this variant is listed in the Catalogue of Somatic Mutations in Cancer (COSMIC accession: COSM253279, COSM253280) and found in several types of carcinoma, glioma and angiosarcoma. Moreover, this variant is not present in frequency databases (gnomAD, Exome Variant Server) and several prediction tools (PolyPhen2, SIFT, LRT, MutationTaster, etc) agree to predict this change as deleterious. Overall, the c.1030G>A p.(Val344Met) variant meets our criteria to be classified as pathogenic.