Submissions for variant NM_004360.5(CDH1):c.2074G>A (p.Ala692Thr)

gnomAD frequency: 0.00003  dbSNP: rs376854556

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199731	SCV000254817	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 692 of the CDH1 protein (p.Ala692Thr). This variant is present in population databases (rs376854556, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 133848). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx	RCV000656823	SCV000329233	uncertain significance	not provided	2018-08-07	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.2074G>A at the cDNA level, p.Ala692Thr (A692T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant was observed in at least one individual with early-onset colorectal cancer (Pearlman 2016), and was also identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in the latter study were younger than 50 years old, thus the unaffected status of this individual may not be significant. CDH1 Ala692Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the extracelluar domain Cadherin 5 (Brooks-Wilson 2004, Figueiredo 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDH1 Ala692Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000574554	SCV000666279	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing	The p.A692T variant (also known as c.2074G>A), located in coding exon 13 of the CDH1 gene, results from a G to A substitution at nucleotide position 2074. The alanine at codon 692 is replaced by threonine, an amino acid with similar properties. This alteration was detected in 1/450 patients diagnosed with colorectal cancer before the age of fifty (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471) and also in a cohort of 681 ancestrally diverse, healthy subjects who underwent whole genome sequencing (Bodian DL et al. PLoS ONE 2014 Apr;9(4):e94554). This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health	RCV000574554	SCV000911989	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 692 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 27978560). This variant has been identified in 7/277130 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.
Mendelics	RCV000199731	SCV001140148	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
ITMI	RCV000120502	SCV000084655	not provided	not specified	2013-09-19	no assertion provided	reference population
GenomeConnect - Invitae Patient Insights Network	RCV000199731	SCV004037485	not provided	Hereditary diffuse gastric adenocarcinoma		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 06-15-2015 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.