ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.304G>A (p.Ala102Thr)

gnomAD frequency: 0.00003  dbSNP: rs368492235
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328228 SCV001142223 benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-10 reviewed by expert panel curation The c.304G>A variant has an allele frequency of 0.00188 (0.19%, 58/30,780 alleles) in the South Asian subpopulation of the gnomAD 2.1.1 cohort (BS1; http://gnomad.broadinstitute.org). The variant was observed in the homozygous state in gnomAD 2.1.1 (BP2). 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; SCV000210895.12; SCV000186827.5). Therefore, 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): BS1, BS2, BP2 .
Ambry Genetics RCV000131780 SCV000186827 likely benign Hereditary cancer-predisposing syndrome 2019-06-11 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.
GeneDx RCV000586036 SCV000210895 likely benign not provided 2019-12-13 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26911350)
Illumina Laboratory Services, Illumina RCV000374968 SCV000398548 benign Hereditary diffuse gastric adenocarcinoma 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl RCV000374968 SCV000487817 uncertain significance Hereditary diffuse gastric adenocarcinoma 2015-11-17 criteria provided, single submitter clinical testing
Invitae RCV000374968 SCV000557409 benign Hereditary diffuse gastric adenocarcinoma 2024-02-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212348 SCV000698394 benign not specified 2020-12-18 criteria provided, single submitter clinical testing Variant summary: CDH1 c.304G>A (p.Ala102Thr) 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 0.00023 in 251274 control chromosomes, predominantly at a frequency of 0.0019 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 67 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 South Asian origin. c.304G>A has been reported in the literature in individuals undergoing multi gene panel based testing for cancer (example, Mannan_2016, Mehmet Akcay_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer or Lobular Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories and one expert panel (ClinGen CDH1 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=6). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health RCV000131780 SCV000902772 benign Hereditary cancer-predisposing syndrome 2016-07-18 criteria provided, single submitter clinical testing
Mendelics RCV000374968 SCV001140130 benign Hereditary diffuse gastric adenocarcinoma 2023-08-22 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000586036 SCV002009851 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212348 SCV002046296 benign not specified 2020-10-09 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000131780 SCV002529169 benign Hereditary cancer-predisposing syndrome 2021-07-27 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212348 SCV002760850 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000374968 SCV003927016 benign Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing BS1; BS2; BP2_Strong (PMID: 30311375)
Myriad Genetics, Inc. RCV000374968 SCV004019601 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-03-06 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.
PreventionGenetics, part of Exact Sciences RCV003917425 SCV004728013 likely benign CDH1-related disorder 2023-08-17 criteria provided, single submitter 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).
Pediatric Oncology, Johns Hopkins University RCV000586036 SCV001147032 likely benign not provided 2019-02-15 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354841 SCV001549552 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 p.Ala102Thr variant was identified in 1 of 282 proband chromosomes (frequency: 0.004) from individuals or families with breast or ovarian cancer (Mannan 2016). The variant was also identified in dbSNP (ID: rs368492235) as "With Uncertain significance", and in ClinVar (classified as likely benign by Invitae, GeneDx and Integrated Genetics/Laboratory Corporation of America; as uncertain significance by Ambry Genetics and Counsyl). The variant was identified in control databases in 60 of 246028 chromosomes (1 homozygous) at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15302 chromosomes (freq: 0.00007), European in 1 of 111500 chromosomes (freq: 0.000009), and South Asian in 58 of 30780 chromosomes (freq: 0.002); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Ala102 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. This variant is classified as a variant of uncertain significance.

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