Submissions for variant NM_004360.5(CDH1):c.1137G>A (p.Thr379=)

dbSNP: rs587783050

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328240	SCV000864619	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-29	reviewed by expert panel	curation	The c.1137G>A p.(Thr379=) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 15831593). Additionally, this variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 15831593, 17545690, 17221870, 21681551, 27995193). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS3, PS4.
Ambry Genetics	RCV000162417	SCV000212757	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-14	criteria provided, single submitter	clinical testing	The c.1137G>A mutation (also known as p.T379T) is located in coding exon 8 of the CDH1 gene. This mutation results from a G to A substitution at nucleotide position 1137. This alteration occurs in the last nucleotide of coding exon 8, adjacent to the canonical splice donor site, and leads to the generation of an alternately spliced transcript harboring a premature stop codon (Karam R et al. Oncogene. 2008 Jul;27:4255-60; Ambry internal data). This mutation has been observed in multiple HDGC families (Lynch HT et al. Fam Cancer. 2011 Dec;10:667-72; More H et al. Hum. Mutat. 2007 Feb;28:203; Kaurah P et al. JAMA. 2007 Jun;297:2360-72; Pantelis D et al. Int J Colorectal Dis. 2016 Dec;31:1825-1833), including one family where this mutation segregated with disease through two generations and was also found in three family members with both gastric cancer and cleft lip and palate, and another family member with gastric cancer and cleft lip (Frebourg T et al. J. Med. Genet. 2006 Feb;43:138-42). It was also seen in a patient with invasive ductal triple negative breast cancer and in her aunt with bilateral lobular breast cancer (Schubert S et al. Int. J. Cancer. 2019 Jun;144(11):2683-2694). Based on the available evidence to date, this alteration is classified as a pathogenic mutation.
Counsyl	RCV000144593	SCV000488913	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2016-07-19	criteria provided, single submitter	clinical testing
Invitae	RCV000144593	SCV000545366	pathogenic	Hereditary diffuse gastric adenocarcinoma	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change affects codon 379 of the CDH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDH1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of hereditary diffuse gastric cancer (PMID: 15831593, 17221870, 17545690, 19725995, 21681551, 23709761, 26025002, 27682646; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156499). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in aberrant splicing, leading to expression of several defective alternate splicing products and high levels of allelic expression imbalance of the CDH1 gene and introduces a premature termination codon (PMID: 15831593, 18427545, 19965908). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000520174	SCV000617360	pathogenic	not provided	2023-03-24	criteria provided, single submitter	clinical testing	Variant at the last nucleotide of an exon predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Frebourg et al., 2006; Karam et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26025002, 19965908, 17221870, 19725995, 21681551, 15831593, 21271559, 28117042, 27682646, 28281021, 22225527, 20373070, 19269290, 29468433, 17545690, 23709761, 26182300, 30311375, 32362280, 30426508, 34949788, 30745422, 31514334, 27995193, 18427545)
Color Diagnostics, LLC DBA Color Health	RCV000162417	SCV000904695	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the last nucleotide of exon 8 of the CDH1 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. Functional RNA studies using patient-derived cells have shown that this variant causes a complex aberrant splicing affecting exon 8 (PMID: 15831593, 18427545, 19965908). This variant has been reported in multiple individuals affected with diffuse gastric cancer (PMID: 15831593, 17221870, 17545690, 21271559, 21681551, 23709761, 27682646, 32362280) and lobular breast cancer (PMID: 30426508). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000520174	SCV001449799	pathogenic	not provided	2015-02-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000144593	SCV001774472	pathogenic	Hereditary diffuse gastric adenocarcinoma	2021-07-11	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1137G>A (p.Thr379Thr) alters a conserved nucleotide located as the last nucleotide of exon 8 adjacent to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in a complex aberant pattern of alternatively spliced transcripts (example, Frebourg_2006). The variant was absent in 251452 control chromosomes. c.1137G>A has been reported in the literature in multiple individuals from families affected with Hereditary Diffuse Gastric Cancer (example, Frebourg_2006, Kaurah_2007, More_2007, Niemeyer_2020). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and one expert panel (ClinGen CDH1 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=6 to include the expert panel)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV000144593	SCV002579270	pathogenic	Hereditary diffuse gastric adenocarcinoma	2021-08-23	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV002467442	SCV002762808	pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PS4_STR, PS3, PM2_SUP, PP1
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000144593	SCV003926733	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PVS1_Moderate; PS3; PS4; PM2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000144593	SCV004020028	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-03-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data,17726045, 15831593]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [17545690, 17221870, 21681551].
Institute of Human Genetics, University of Leipzig Medical Center	RCV000144593	SCV004027636	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-05-16	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PS1_SUP,PM2_SUP, PS3
CeGaT Center for Human Genetics Tuebingen	RCV000520174	SCV004704425	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CDH1: PS4, PM2, PVS1:Moderate, PP1, PS3:Supporting
OMIM	RCV000013036	SCV000033281	pathogenic	Gastric cancer, familial diffuse, and cleft lip with or without cleft palate	2006-02-01	no assertion criteria provided	literature only
Pathway Genomics	RCV000144593	SCV000189919	pathogenic	Hereditary diffuse gastric adenocarcinoma	2014-07-24	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000144593	SCV002075185	not provided	Hereditary diffuse gastric adenocarcinoma		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 08-12-2019 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.