Submissions for variant NM_004360.5(CDH1):c.1315G>A (p.Ala439Thr)

gnomAD frequency: 0.00001  dbSNP: rs758764445

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164296	SCV000214926	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	The p.A439T variant (also known as c.1315G>A), located in coding exon 9 of the CDH1 gene, results from a G to A substitution at nucleotide position 1315. The alanine at codon 439 is replaced by threonine, an amino acid with similar properties. This variant was identified in a cohort of individuals with metastatic breast cancer who underwent germline testing of 30 genes and was classified as a variant of unknown significance by authors (Stuttgen K et al. JAMA Oncol, 2019 Oct;5:1506-1508). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168147	SCV000218808	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-05-19	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 184950). This missense change has been observed in individual(s) with breast cancer (PMID: 31465090). This variant is present in population databases (rs758764445, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 439 of the CDH1 protein (p.Ala439Thr).
GeneDx	RCV000218750	SCV000278914	uncertain significance	not provided	2018-02-14	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.1315G>A at the cDNA level, p.Ala439Thr (A439T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Ala439Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). CDH1 Ala439Thr is located in the Cadherin 3 domain (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether CDH1 Ala439Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Illumina Laboratory Services, Illumina	RCV000168147	SCV000398565	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000168147	SCV000488681	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164296	SCV000908736	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 439 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 3/251470 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV000168147	SCV004020005	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-06	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003462129	SCV004215720	uncertain significance	Familial cancer of breast	2023-05-28	criteria provided, single submitter	clinical testing