Submissions for variant NM_004360.5(CDH1):c.208dup (p.Ser70fs)

dbSNP: rs1555514406

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328396	SCV001142231	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-29	reviewed by expert panel	curation	The c.208dup p.(Ser70Phefs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two family meeting HDGC clinical criteria (PS4_Moderate; SCV000637771.2, SCV000779081.2). 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_Moderate, PM5_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545409	SCV000637771	pathogenic	Hereditary diffuse gastric adenocarcinoma	2018-02-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser70Phefs*24) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 463742). Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657349	SCV000779081	likely pathogenic	not provided	2017-06-21	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in CDH1 is denoted c.208dupT at the cDNA level and p.Ser70PhefsX24 (S70FfsX24) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ATTTT[dupT]CCCT. The duplication causes a frameshift which changes a Serine to a Phenylalanine at codon 70, and creates a premature stop codon at position 24 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000545409	SCV003927002	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PVS1; PS4_Moderate; PM2 (PMID: 30311375)