Submissions for variant NM_004360.5(CDH1):c.1849G>A (p.Ala617Thr)

gnomAD frequency: 0.01412  dbSNP: rs33935154

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328148	SCV000864628	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-08	reviewed by expert panel	curation	The c.1849G>A (p.Ala617Thr) variant has an allele frequency of 0.04479 (4.5%, 1,076/24,022 alleles) in the African subpopulation of the gnomAD cohort (BA1). In summary, 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): BA1.
GeneDx	RCV000120500	SCV000167597	benign	not specified	2013-10-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000130292	SCV000185140	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Pathway Genomics	RCV000013019	SCV000223773	benign	Hereditary diffuse gastric adenocarcinoma	2014-10-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120500	SCV000225610	benign	not specified	2015-01-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013019	SCV000261924	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000130292	SCV000267032	benign	Hereditary cancer-predisposing syndrome	2016-01-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000013019	SCV000398570	likely benign	Hereditary diffuse gastric adenocarcinoma	2017-04-27	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.
Counsyl	RCV000013019	SCV000488401	benign	Hereditary diffuse gastric adenocarcinoma	2016-03-23	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130292	SCV000576454	likely benign	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130292	SCV000684383	benign	Hereditary cancer-predisposing syndrome	2015-03-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120500	SCV000806645	benign	not specified	2016-12-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034706	SCV000885159	benign	not provided	2023-09-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798001	SCV002043258	benign	Breast and/or ovarian cancer	2021-05-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130292	SCV002529093	benign	Hereditary cancer-predisposing syndrome	2020-03-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120500	SCV002551784	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490357	SCV002794917	benign	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2021-08-25	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	RCV000013019	SCV003926862	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BA1 (PMID: 30311375)
CeGaT Center for Human Genetics Tuebingen	RCV000034706	SCV004010505	benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BS1, BS2
Myriad Genetics, Inc.	RCV000013019	SCV004020039	benign	Hereditary diffuse gastric adenocarcinoma	2023-03-07	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Breakthrough Genomics, Breakthrough Genomics	RCV000034706	SCV005251516	benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000013018	SCV000033263	pathogenic	Endometrial carcinoma	2003-03-01	no assertion criteria provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034706	SCV000043247	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120500	SCV000084653	not provided	not specified	2013-09-19	no assertion provided	reference population
Mayo Clinic Laboratories, Mayo Clinic	RCV000120500	SCV000691824	benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000130292	SCV000787978	benign	Hereditary cancer-predisposing syndrome	2017-10-10	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356764	SCV001552021	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Ala617Thr variant was identified in 7 of 540 proband chromosomes (frequency: 0.013) from individuals or families with osteoblastic osteosarcoma, gastric adenocarcinoma, breast cancer and was present in 14 (all in African American) of 716 (516 African American) control chromosomes (frequency: 0.02) from healthy individuals (Choy 2012, El-Husny 2014, Suriano 2003, Valente 2014). The variant was also identified in dbSNP (ID: rs33935154) as With Pathogenic allele, ClinVar (classified as benign by GeneDx, Ambry Genetics, Pathway Genomics, Invitae, Vantari Genetics, Coulsyl; classified as pathogenic by OMIM), Clinvitae (conflicting interpretations of pathogenicity by ClinVar), Cosmic (neutral), databases. The variant was not identified in MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 1211(25 homozygous) of 277184 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1076 of 24022 chromosomes (freq: 0.045). The p.Ala617 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Cadherin Cadherin-like functional domain increasing the liklihood that it may have clinical significance. Functional analysis by Suriano (2003) identified cells expressing the Ala617Thr mutation showed the same non-invasive behavior as cells expressing wild-type protein. The case study by Lajus (2015) found the variant in a family with no history of diffuse gastric cancer. The daughter diagnosed with in situ breast cancer does not carry the CDH1 mutation. The index case (72 year old) is alive without the evidence of breast or gastric cancer, and is on surveillance. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000120500	SCV001807351	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000120500	SCV001920376	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120500	SCV001956047	benign	not specified		no assertion criteria provided	clinical testing
OMIM	RCV004579518	SCV005062056	pathogenic	DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME	2003-03-01	no assertion criteria provided	literature only