Submissions for variant NM_004360.5(CDH1):c.2095C>T (p.Gln699Ter)

dbSNP: rs121964874

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328152	SCV001365436	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-25	reviewed by expert panel	curation	The c.2095C>T (p.Gln699Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 9537325). 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, PM2_Supporting, PS4_Supporting, PM5_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013024	SCV002234263	pathogenic	Hereditary diffuse gastric adenocarcinoma	2024-02-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln699*) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with diffuse gastric cancer (PMID: 9537325). ClinVar contains an entry for this variant (Variation ID: 12237). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000013024	SCV003926890	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PVS1; PS4_Supporting; PM2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000013024	SCV004044510	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005364875	SCV005916203	pathogenic	Familial cancer of breast; Ovarian cancer	2022-02-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV005305944	SCV005981477	pathogenic	Hereditary cancer-predisposing syndrome	2025-02-05	criteria provided, single submitter	clinical testing	The p.Q699* pathogenic mutation (also known as c.2095C>T), located in coding exon 13 of the CDH1 gene, results from a C to T substitution at nucleotide position 2095. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This variant was reported in individual(s) with features consistent with CDH1-related diffuse gastric and lobular breast cancer (DGLBC) (Guilford P et al. Nature, 1998 Mar;392:402-5; More H et al. Hum Mutat, 2007 Feb;28:203; Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000013024	SCV000033269	pathogenic	Hereditary diffuse gastric adenocarcinoma	1998-03-26	no assertion criteria provided	literature only