Submissions for variant NM_004360.5(CDH1):c.671G>A (p.Arg224His)

gnomAD frequency: 0.00003  dbSNP: rs201511530

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328162	SCV001943347	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-09	reviewed by expert panel	curation	The c.671G>A (p.Arg224His) missense variant has a frequency of 0. 0.00003189 (8 of 250,850) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00006179 (7 of 113,278) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >50 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; SCV000637843.5, SCV000278911.9). This variant was observed in the homozygous state in an individual without DGC, SRC tumors or LBC and whose family does not suggest HDGC (BP2_Strong, internal laboratory contributor). In summary, the clinical significance of this variant is classified as benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong.
Ambry Genetics	RCV000129943	SCV000184762	likely benign	Hereditary cancer-predisposing syndrome	2020-06-18	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	RCV000034708	SCV000278911	uncertain significance	not provided	2021-12-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, or prostate cancer (Lu 2015, Hauke 2018, Huang 2018); This variant is associated with the following publications: (PMID: 22703879, 25583476, 26689913, 27720647, 26486520, 26517685, 28135145, 25503501, 29522266, 15235021, 22850631, 29625052)
Illumina Laboratory Services, Illumina	RCV000320751	SCV000398553	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-01-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216097	SCV000600995	uncertain significance	not specified	2017-02-23	criteria provided, single submitter	clinical testing
Invitae	RCV000320751	SCV000637843	benign	Hereditary diffuse gastric adenocarcinoma	2024-01-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000320751	SCV000785439	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-08-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000320751	SCV000839079	benign	Hereditary diffuse gastric adenocarcinoma	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129943	SCV000902871	likely benign	Hereditary cancer-predisposing syndrome	2016-10-12	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000320751	SCV001775509	benign	Hereditary diffuse gastric adenocarcinoma	2021-02-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129943	SCV002529203	likely benign	Hereditary cancer-predisposing syndrome	2021-03-29	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	RCV000320751	SCV003926674	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BP2_Strong; BS2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000320751	SCV004020055	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-07	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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034708	SCV000043243	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.