ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.88C>A (p.Pro30Thr) (rs139866691)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000123256 SCV000864601 benign Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation 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: BA1, BS2.
GeneDx RCV000120508 SCV000149773 likely benign not specified 2018-01-18 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000123256 SCV000166563 benign Hereditary diffuse gastric cancer 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115864 SCV000172834 benign Hereditary cancer-predisposing syndrome 2014-08-07 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
Illumina Clinical Services Laboratory,Illumina RCV000123256 SCV000398547 likely benign Hereditary diffuse gastric cancer 2017-04-27 criteria provided, single submitter clinical testing 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.
Counsyl RCV000123256 SCV000488726 likely benign Hereditary diffuse gastric cancer 2016-05-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115864 SCV000537410 likely benign Hereditary cancer-predisposing syndrome 2015-10-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000120508 SCV000538647 likely benign not specified 2016-03-29 criteria provided, single submitter clinical testing 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.
Genetic Services Laboratory, University of Chicago RCV000120508 SCV000593911 likely benign not specified 2016-10-05 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000586357 SCV000806684 likely benign not provided 2017-03-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000586357 SCV000885153 likely benign not provided 2018-01-30 criteria provided, single submitter clinical testing The p.Pro30Thr variant (rs139866691) has been reported in several disease cohorts including orofacial clefts (Vogelaar 2013), lobar breast cancer (Schrader 2011), and hereditary diffuse gastric cancer syndrome (Molinaro 2014). However, in each of these cohorts, the frequency of observance is consistent with published general population frequencies. This variant is listed in the NHLBI GO Exome Sequencing Project with a European population frequency of 0.16 percent and is listed in the Genome Aggregation Database (gnomAD) with a European population frequency of 0.2 percent. Functional studies on the effect of the p.Pro30Thr variant have thus far yielded inconclusive results more suggestive of a very mild effect, if any effect at all, on CDH1 function (Schrader 2011, Vogelaar 2013). The proline at position 30 is weakly conserved (considering 10 species) (Alamut V2.7.1) and is located in the cadherin prodomain that is cleaved during protein processing (Posthaus 1998). Computational analyses of the effects of the p.Pro30Thr variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: possibly damaging). The p.Pro30Thr variant has also been found in healthy exome controls (Amendola 2015 and Bodian 2014) and has been reported to ClinVar with classifications of benign and likely benign (see link below). Altogether, the p.Pro30Thr variant has been classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586357 SCV000888043 benign not provided 2018-10-09 criteria provided, single submitter clinical testing
Mendelics RCV000123256 SCV001140127 likely benign Hereditary diffuse gastric cancer 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120508 SCV001337977 benign not specified 2020-01-23 criteria provided, single submitter clinical testing 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.
ITMI RCV000120508 SCV000084661 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148455 SCV000190154 likely benign Orofacial cleft 2014-06-01 no assertion criteria provided research
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000123256 SCV000493725 uncertain significance Hereditary diffuse gastric cancer 2016-01-27 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000120508 SCV000691811 uncertain significance not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000115864 SCV000787986 likely benign Hereditary cancer-predisposing syndrome 2017-07-17 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000586357 SCV001549631 likely benign not provided no assertion criteria provided clinical testing 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.

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