Submissions for variant NM_004360.5(CDH1):c.2638G>A (p.Glu880Lys)

gnomAD frequency: 0.00001  dbSNP: rs34507583

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003993846	SCV004812907	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-09-25	reviewed by expert panel	curation	The c.2638G>A (p.Glu880Lys) variant results in a missense change in the last exon of CDH1. This variant has been reported in at least five individuals meeting criteria for HDGC (PMID: 28522256, 32426482, 34537906, 32241597). However, this variant is present at a maximum frequency of 0.001153 (6 of 5,204 alleles) in the East Asian subpopulation in gnomAD, which is greater than expected for CDH1-related diffuse gastric and lobular breast cancer (BS1). This variant has also been observed in 112 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant is classified as benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2.
Ambry Genetics	RCV000164164	SCV000214782	likely benign	Hereditary cancer-predisposing syndrome	2021-11-15	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	RCV000989628	SCV000288477	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-12-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000479339	SCV000564843	likely benign	not provided	2019-10-15	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32426482, 28522256, 30287823, 28135145)
Color Diagnostics, LLC DBA Color Health	RCV000164164	SCV000684449	benign	Hereditary cancer-predisposing syndrome	2021-01-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000989628	SCV001140157	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030617	SCV001193551	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194010	SCV001363234	benign	not specified	2023-08-07	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2638G>A (p.Glu880Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 276380 control chromosomes, predominantly at a frequency of 0.00087 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 30-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2638G>A has been reported in the literature in individuals affected with cancer, including diffuse gastric cancer, breast cancer, pancreatic ductal adenocarcinoma and colorectal cancer as well as in unaffected controls (example, Momozawa_2018, Cho_2017, Mandelker_2017, Yurgelun_2017, Ohmoto_2016, Choi_2020, Pan_2022). Additionally, three large-scale case-control studies suggest the carrier frequency of this variant is no different as in the breast cancer cohort, the biliary tract cancer cohort and the Hereditary Colorectal Cancer, respectively (example, Momozawa_2018, Fujita_2020, Okawa_2023). At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (PTEN c.423delT, p.Arg142GlyfsX5), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant through usage of slow aggregation assays demonstrating that cells overexpressing the variant of interest aggregated as efficiently as did wild-type CDH1-overexpressing cells (Cho_2017). The following publications have been ascertained in the context of this evaluation (PMID: 32241597, 26692440, 33309985, 28873162, 30287823, 28522256, 34537906, 28135145, 36243179). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus classification of benign/likely benign (Benign, n=1; likely benign, n=4; VUS, n=2). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000164164	SCV002529163	likely benign	Hereditary cancer-predisposing syndrome	2021-07-16	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355037	SCV001549799	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Glu880Lys variant was identified in 2 of 160 proband chromosomes (frequency: 0.0125) from individuals or families with sporadic diffuse gastric cancer (Cho 2017). The variant was identified in dbSNP (rs34507583) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Color, Ambry Genetics and GeneDx and likely benign by Invitae). The variant was identified in control databases in 22 of 251,400 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 16 of 18,394 chromosomes (freq: 0.0009), Latino in 4 of 34,592 chromosomes (freq: 0.0001), South Asian in 1 of 30,616 chromosomes (freq: 0.00003), European in 1 of 113,700 chromosomes (freq: 0.000009), while the variant was not observed in the African, Ashkenazi Jewish, Finnish and Other populations. In one study, in vitro expression of the variant had no observed effect on cell aggregation (Cho 2017) The p.Glu880 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003895125	SCV004709606	likely benign	CDH1-related disorder	2022-11-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).