Submissions for variant NM_004360.5(CDH1):c.1162G>A (p.Glu388Lys)

gnomAD frequency: 0.00001  dbSNP: rs372838203

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328164	SCV000864609	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.1162G>A (p.Glu388Lys) variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer, lobular breast cancer (BP2_Strong; SCV000254804.3). The variant has also been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BP2_Strong, BS2.
GeneDx	RCV000656820	SCV000149743	uncertain significance	not provided	2018-01-10	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.1162G>A at the cDNA level, p.Glu388Lys (E388K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has been identified in 1/118 healthy Hispanic individuals undergoing whole genome sequencing (Bodian 2014); of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. CDH1 Glu388Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 evidence, it is unclear whether CDH1 Glu388Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000115834	SCV000216627	likely benign	Hereditary cancer-predisposing syndrome	2019-01-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196601	SCV000254804	benign	Hereditary diffuse gastric adenocarcinoma	2024-01-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000196601	SCV000488292	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-02-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115834	SCV000911103	likely benign	Hereditary cancer-predisposing syndrome	2016-07-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656820	SCV001134048	benign	not provided	2023-02-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115834	SCV002531144	benign	Hereditary cancer-predisposing syndrome	2020-10-15	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000196601	SCV004020060	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-07	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120514	SCV004020968	uncertain significance	not specified	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1162G>A (p.Glu388Lys) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 299176 control chromosomes (gnomAD, Bodian_2014, Momozawa_2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1162G>A has been reported in the literature in individuals affected with breast cancer (e.g. Wang_2019, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 30287823, 30982232, 33471991). Nine ClinVar submitters have assessed the variant since 2014, including one expert panel (ClinGen): two classified the variant as uncertain significance, two as likely benign, and five as benign (including the expert panel). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
ITMI	RCV000120514	SCV000084667	not provided	not specified	2013-09-19	no assertion provided	reference population
Genetic Services Laboratory, University of Chicago	RCV000120514	SCV003839325	benign	not specified	2022-08-22	no assertion criteria provided	clinical testing