ClinVar Miner

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

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Total submissions: 12
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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 Neoplasm of the breast 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 Uterine cervical neoplasms 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; 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.

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