ClinVar Genomic variation as it relates to human health

The c.88C>A (p.Pro30Thr) variant has an allele frequency of 0.00249 (0.25%, 178/71372 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). In addition to meeting stand along criteria for a benign classification, this variant has also been seen in >900 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): BA1, BS2.

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.

Variant summary: CDH1 c.88C>A (p.Pro30Thr) results in a non-conservative amino acid change located in the Cadherin prodomain (IPR014868) 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 0.0013 in 156216 control chromosomes. The observed variant frequency is approximately 47 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.88C>A has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MUTYH c.1227_1228dupGG, p.Glu410Glyfs*43; CTNNA1 c.76delGA, p.Arg27ThrfsX17; CHEK2 c.1100delC, p.T367fs*15), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating reduced localization of the variant protein to the plasma membrane, slightly decreased cell aggregation and minor increase in the invasion capacity of cells expressing the variant however, these results do not allow convincing conclusions about the variant effect (Vogelaar 2012). Thirteen clinical diagnostic laboratories and an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (12x benign/likely benign, 1x VUS, expert panel benign). Based on the evidence outlined above, the variant was classified as benign.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25593300, 29958926, 26483394, 29348693, 29589180, 26022348, 27616075, 28944238, 27978560, 25637381, 28135145, 15831593, 10094558, 27443514, 27153395, 26759166, 27146957, 26976419, 26123647, 26072394, 25980754, 12800196, 20921021, 24493355, 23197654, 22470475, 24728327, none)

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.

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Detected in 2 patients with orofacial clefts (Vogelaar 2013). Gene is strongly asociated with gastric cancer, there is limited evidence for association with orofacial clefts.

BA1; BS2 (PMID: 30311375)

This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.

CDH1: BS1

The CDH1 p.Pro30Thr variant was identified in 5 of 3312 proband chromosomes (frequency: 0.0015) from individuals or families with lobular breast cancer and Lynch syndrome and was present in 11 of 17412 control chromosomes (frequency: 0.0006) from healthy individuals (Molinaro 2014, Sarrio 2003, Schrader 2011, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs139866691) as “With other allele”, ClinVar (as benign by Invitae and Ambry Gentics, likely benign by GeneDx, Illumina, Counsyl, Color Genomics, Laboratory for Molecular Medicine, University of Chicago, and University of Washington Medical Center, and as uncertain significance by Knight Diagnostic Laboratories), Clinvitae (4x with conflicting interpretations of pathogenicity), Cosmic (seen in breast cancer), Insight Colon Cancer Gene Variant Database (2x), and Zhejiang Colon Cancer Database (2x). The variant was not identified in the MutDB database. The variant was identified in control databases in 232 of 178576 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 3 of 15728 chromosomes (freq: 0.0002), Other in 11 of 4718 chromosomes (freq: 0.002), Latino in 31 of 24390 chromosomes (freq: 0.001), European in 178 of 71372 chromosomes (freq: 0.002), Finnish in 3 of 19552 chromosomes (freq: 0.0002), and South Asian in 6 of 22566 chromosomes (freq: 0.0003), while the variant was not observed in the Ashkenazi Jewish or East Asian populations. In a functional study in which RT-PCR was performed, the protein transcript was found to be normal (Molinaro 2014). A study of CDH1 variants in Hereditary Diffuse Gastric Cancer (HDGC) patients using in silico tools concluded the variant was structurally tolerated (Simoes Correia 2012). The variant was also found in 2 patients with orofacial clefts; during embryonic development, the cell adhesion molecule E-cadherin, encoded by CDH1, is highly expressed in the median edge epithelium of the palate (Vogelaar 2013). The p.Pro30 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, HumanSpliceFinder) 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.