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

gnomAD frequency: 0.00003  dbSNP: rs368492235

Total submissions: 18

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
Labcorp Genetics (formerly Invitae), Labcorp	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.
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.
PreventionGenetics, part of Exact Sciences	RCV003917425	SCV004728013	likely benign	CDH1-related disorder	2023-08-17	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).