Submissions for variant NM_006218.4(PIK3CA):c.1030G>A (p.Val344Met) (rs1057519942)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485942	SCV000569339	likely pathogenic	not provided	2016-02-25	criteria provided, single submitter	clinical testing	The V344M variant in the PIK3CA gene has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in cancers of the endometrium, ovary, lung, and colon (Cheung et al., 2011; Jones et al., 2012; Kanagal-Shamanna et al., 2014; Haley et al., 2015). The V344M variant was not observed in approximately 5900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The V344M variant is a strong candidate for a pathogenic variant.
Invitae	RCV000631216	SCV000752230	pathogenic	Cowden syndrome	2017-08-18	criteria provided, single submitter	clinical testing	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. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with megalencephaly (PMID: 27631024). ClinVar contains an entry for this variant (Variation ID: 376498). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
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
Database of Curated Mutations (DoCM)	RCV000433184	SCV000507122	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444028	SCV000507123	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423160	SCV000507124	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433868	SCV000507125	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443225	SCV000507126	likely pathogenic	Non-Hodgkin lymphoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427369	SCV000507127	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438004	SCV000507128	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443321	SCV000507129	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
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.