Submissions for variant NM_004360.5(CDH1):c.604G>A (p.Val202Ile)

gnomAD frequency: 0.00001  dbSNP: rs546716073

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328188	SCV000864590	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-08	reviewed by expert panel	curation	The c.604G>A (p.Val202Ile) variant has an allele frequency of 0.00354 (0.35%, 109/30,772 alleles) in the South Asian 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.
Ambry Genetics	RCV000129079	SCV000183782	benign	Hereditary cancer-predisposing syndrome	2017-10-17	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.
GeneDx	RCV000588677	SCV000210899	likely benign	not provided	2020-10-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23431106, 24728327, 28135048, 26182300, 21696387)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226583	SCV000288490	benign	Hereditary diffuse gastric adenocarcinoma	2025-02-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000226583	SCV000398552	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588677	SCV000698404	benign	not provided	2016-05-03	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 variant, c.604G>A (p.Val202Ile) causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a "benign"outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 72/121206 (1/1683 including 1 homozygote), predominantly in the South Asian cohort, 64/16478 (1/257 including 1 homozygote), which exceeds the estimated maximum expected allele frequency for a pathogenic CDH1 variant of 1/35335. Therefore, suggesting that the variant is a common polymorphism found in population(s) of South Asian origins. The variant of interest has been reported in affected individuals via publication(s) including a publication indicating a MLH1 variant is causal for the phenotype, not the variant of interest. Multiple reputable clinical laboratories have cited the variant with conflicting classifications, "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence, therefore the variant of interest is classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588677	SCV000888036	benign	not provided	2023-05-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129079	SCV000902689	benign	Hereditary cancer-predisposing syndrome	2016-11-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129079	SCV002529197	benign	Hereditary cancer-predisposing syndrome	2020-10-06	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315743	SCV004017016	benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120512	SCV004026633	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129079	SCV004228129	benign	Hereditary cancer-predisposing syndrome	2023-09-21	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000226583	SCV005880660	benign	Hereditary diffuse gastric adenocarcinoma	2025-02-01	criteria provided, single submitter	clinical testing
ITMI	RCV000120512	SCV000084665	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000588677	SCV001553267	likely benign	not provided		no assertion criteria provided	clinical testing	The CDH1 p.Val202Ile variant was identified in the literature in 1 of 472 proband chromosomes (frequency: 0.002) from individuals or families with gastric cancer and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Chen 2013, Bodian 2014). The variant was also identified in the following databases: dbSNP (ID: rs546716073) as "With Uncertain significance, other allele" and ClinVar (classified as likely benign by Ambry Genetics, GeneDx, and Illumina Clinical Services Laboratory; and as benign by Invitae). The variant was not identified in Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 126 of 276950 chromosomes (1 homozygous) at a frequency of 0.0005 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: South Asian in 109 of 30772 chromosomes (freq: 0.004), Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34408 chromosomes (freq: 0.00003), and East Asian in 15 of 18866 chromosomes (freq: 0.0008), while the variant was not observed in the African, European, Ashkenazi Jewish, or Finnish populations. The variant was observed in a patient with gastric cancer as co-occurring with a pathogenic variant in MLH1 (Chen 2013) and was identified by our laboratory in an individual that also carried a pathogenic variant in PMS2, increasing the likelihood that this is a benign variant. The p.Val202 residue is not conserved in mammals and 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 greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000120512	SCV001923612	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120512	SCV001958156	benign	not specified		no assertion criteria provided	clinical testing