Submissions for variant NM_004360.5(CDH1):c.1865A>G (p.Asn622Ser)

gnomAD frequency: 0.00004  dbSNP: rs147925149

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328192	SCV001943360	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.1865A>G (p.Asn622Ser) missense variant has a frequency of 0.000007953 (2 of 251,480) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00006152 (1 of 16,256) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >10 (27) individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; SCV000166547.6, SCV000329232.7). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Invitae	RCV000123241	SCV000166547	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131244	SCV000186201	likely benign	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000286705	SCV000329232	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631)
Counsyl	RCV000123241	SCV000488709	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-05-25	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000123241	SCV000890923	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2020-09-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000286705	SCV001134069	likely benign	not provided	2022-09-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131244	SCV001348201	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 622 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 2/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824619	SCV002074187	uncertain significance	not specified	2022-01-10	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	RCV000123241	SCV003926863	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000123241	SCV004020021	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.