ClinVar Genomic variation as it relates to human health

The c.2413G>A (p.Asp805Asn) variant has an allele frequency of 0.00207 (0.21%, 21/10,148 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort (BA1). 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): BA1.

Variant summary: CDH1 c.2413G>A (p.Asp805Asn) results in a conservative amino acid change located in the Cadherin, cytoplasmic domain (IPR000233) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 251938 control chromosomes. The observed variant frequency is approximately 9 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 benign. c.2413G>A has been reported in the literature in a family with gastric and diffuse gastric cancer in an unaffected patient; however the age was not provided (Hansford_2015). An additional CDH1 variant (c.2430delT) was also identified in a proband affected with DGC in this family. This variant was also observed associated with non-syndromic cleft-palate, Lynch Syndrome, pancreatic ductal adenocarcinoma, and NSCLC patients without strong evidence for causality (Vogelaar_2013, Yurgelun_2015, Yurgelun_2017, Rangachari_2015, Shindo_2017, Shirts_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.7618-1G>A), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Vogelaar_2013). The most pronounced variant effect results in slightly impaired cell invasion suppression, displaying smaller cellular aggregates than the WT and to result in reduced membranous E-cadherin expression while not affecting the expression level of CDH1. However, the clinical relevance of these functional impacts is uncertain. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments with a majority consensus leaning towards benign/likely benign (n=8). Based on the evidence outlined above, the variant was classified as benign.

This variant is associated with the following publications: (PMID: 29348693, 25980754, 25862857, 24728327, 25637381, 26601054, 26845104, 26580448, 26182300, 23197654, 28135145, 28873162, 28767289)

This alteration is classified as 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.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

BA1; BS2_Suportive (PMID: 30311375)

CDH1: BP1, BS1, BS2

Originally interpreted based on literature review PMID: 25637381. Found in a female patient having exome sequencing for an unrelated indication. No known history of diffuse gastric cancer or breast cancer.

The CDH1 p.Asp805Asn variant was identified in 2 of 2886 proband chromosomes (frequency: 0.0007) from individuals or families with hereditary diffuse gastric cancer or Lynch syndrome and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Bodian 2014, Hansford 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs200894246) as "With other allele", ClinVar (classified as benign by Invitae; as likely benign by GeneDx and Ambry Genetics; as uncertain significance by four submitters). The variant was identified in control databases in 63 of 276968 chromosomes at a frequency of 0.0002 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: Other in 2 of 6460 chromosomes (freq: 0.0003), Latino in 13 of 34404 chromosomes (freq: 0.0004), European in 26 of 126584 chromosomes (freq: 0.0002), Ashkenazi Jewish in 21 of 10148 chromosomes (freq: 0.002), and South Asian in 1 of 30770 chromosomes (freq: 0.00003), while the variant was not observed in the African, East Asian, and Finnish, populations. One study performed in vitro functional assay (Vogelaar 2013) and found that the variant p.Asp805Asn affects E-cadherin protein function and its subcellular localization and can be considered as a pathogenic mutation however result have no additional functional work supports this claim and more over this missense variant and similar ones in this study have been found in families without a clinical phenotype suggesting that the in vitro data does not reflect the clinical impact of the variants. The p.Asp805 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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).

Variant interpreted as Uncertain significance and reported on 04-08-2016 by Lab Quest Diagnostics. 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.