Submissions for variant NM_004360.5(CDH1):c.2204C>T (p.Ala735Val)

gnomAD frequency: 0.00003  dbSNP: rs587782464

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003993822	SCV004812903	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2024-03-25	reviewed by expert panel	curation	The NM_004360.5(CDH1):c.2204C>T (p.Ala735Val) is missense variant. The variant has been observed in >10 (188) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; PMID: 26898890; ClinVar: SCVs: SCV000186555.7, SCV000260700.10, SCV000210926.16; internal lab contributors). CDH1-VCEP recommended a variant to reach likely benign classification based on BS2 alone. Therefore, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Ambry Genetics	RCV000131554	SCV000186555	likely benign	Hereditary cancer-predisposing syndrome	2022-01-27	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	RCV000656824	SCV000210926	uncertain significance	not provided	2024-01-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25734694, 22941188, 26976419, 26486520, 25502898, 32658311, 15235021, 22850631, 33471991, 36436516, 26898890)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206685	SCV000260700	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000206685	SCV000488625	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-05-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212382	SCV000600974	likely benign	not specified	2024-10-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131554	SCV000684407	likely benign	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131554	SCV002529113	likely benign	Hereditary cancer-predisposing syndrome	2022-01-23	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212382	SCV002572414	uncertain significance	not specified	2022-08-29	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2204C>T (p.Ala735Val) results in a non-conservative amino acid change located in the Cadherin, cytoplasmic domain (IPR000233) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 282840 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2204C>T has been reported in the literature in individuals affected with Breast Cancer (e.g. Ackay_2021, Caminsky_2016, Dorling_2021) as well as control individuals (Dorling_2021). The variant was also reported in the FLOSSIES database, consisting of women over the age of 70 with no history of cancer. These data do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: four classify the variant as uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000206685	SCV003926905	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PS4_Supporting (PMID: 30311375)
Myriad Genetics, Inc.	RCV000206685	SCV004020006	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.