Submissions for variant NM_004360.5(CDH1):c.214G>A (p.Asp72Asn)

gnomAD frequency: 0.00006  dbSNP: rs35606263

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328194	SCV004035095	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-03	reviewed by expert panel	curation	The c.214G>A (p.Asp72Asn) missense variant has a maximum subpopulation frequency of 0.048% in the gnomAD v2.1.1 cohort (http://gnomad.broadinstitute.org). This variant has been observed in over 300 probands not meeting HDGC phenotype criteria (BS2; SCV000210893.13, SCV000186096.8, SCV000166549.12). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023)
Invitae	RCV000123243	SCV000166549	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131154	SCV000186096	likely benign	Hereditary cancer-predisposing syndrome	2019-12-09	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	RCV000656818	SCV000210893	likely benign	not provided	2021-02-25	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with lung cancer and in 1/11,241 controls but not in the associated breast cancer cases (Momozawa 2018, Santeufemia 2019); This variant is associated with the following publications: (PMID: 30287823, 30979070, 31159747, 31784482)
Counsyl	RCV000123243	SCV000488289	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-02-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656818	SCV000600973	likely benign	not provided	2023-01-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000656818	SCV000806654	uncertain significance	not provided	2017-05-12	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000131154	SCV000821970	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000123243	SCV000839074	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131154	SCV000902795	likely benign	Hereditary cancer-predisposing syndrome	2015-07-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235149	SCV000919098	likely benign	not specified	2024-01-22	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.214G>A (p.Asp72Asn) results in a 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 4.9e-05 in 1607036 control chromosomes, predominantly at a frequency of 0.00045 within the Latino subpopulation in the gnomAD database (v4 dataset). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 16-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 Latino origin. The variant, c.214G>A, has been reported in the literature in individuals affected with breast cancer (Tsaousis_2019, Dorling_2021), but it was also found in several controls (Momozawa_2018, Dorling_2021, Okawa_2023). In addition, this variant was also reported in 3/7325 European American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: NO_PMID, 19011631, 30287823, 31159747, 33471991, 36243179). ClinVar contains an entry for this variant (Variation ID: 136064). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000131154	SCV002529109	likely benign	Hereditary cancer-predisposing syndrome	2021-07-26	criteria provided, single submitter	curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000123243	SCV003927004	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2_Supporting (PMID: 30311375)
Myriad Genetics, Inc.	RCV000123243	SCV004019999	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656818	SCV001550075	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CDH1 p.Asp72Asn variant was not identified in 14102 proband chromosomes from individuals or families with breast cancer but was present in 4 of 22482 control chromosomes (frequency: 0.0009) from healthy individuals (Momozawa 2018). The variant was also identified in dbSNP (ID: rs35606263) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and five other submitters), and LOVD 3.0 (2x as VUS). The variant was identified in control databases in 29 of 277070 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24020 chromosomes (freq: 0.0001), Latino in 17 of 34418 chromosomes (freq: 0.0005), European in 6 of 126588 chromosomes (freq: 0.00005), Ashkenazi Jewish in 3 of 10148 chromosomes (freq: 0.0003); it was not observed in the Other, East Asian, Finnish, or South Asian populations. The p.Asp72 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.