Submissions for variant NM_004360.5(CDH1):c.2100del (p.Val701fs)

dbSNP: rs1555517136

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328434	SCV001142261	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-29	reviewed by expert panel	curation	The c.2100del p.(Val701Serfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 26182300). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). 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	RCV000639209	SCV000760779	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-09-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 492677). This premature translational stop signal has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 26182300). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val701Serfs*21) 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).
Myriad Genetics, Inc.	RCV000639209	SCV004043677	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
GeneDx	RCV000583312	SCV005325768	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30745422, 26182300, 32489267)
Mayo Clinic Laboratories, Mayo Clinic	RCV000583312	SCV000691827	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000583312	SCV001548788	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004722956	SCV005340948	pathogenic	CDH1-related disorder	2024-04-30	no assertion criteria provided	clinical testing	The CDH1 c.2100delT variant is predicted to result in a frameshift and premature protein termination (p.Val701Serfs*21). This variant has been reported in multiple individuals with hereditary diffuse gastric cancer (HDGC) (see for example, eTable 1. Hansford et al 2015. PubMed ID: 26182300; Table 1. Aronson et al 2020. PubMed ID: 32489267). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar by the ClinGen CDH1 Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/492677/). Frameshift variants in CDH1 are expected to be pathogenic. This variant is interpreted as pathogenic.