Submissions for variant NM_004360.5(CDH1):c.1A>G (p.Met1Val)

dbSNP: rs1555509622

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328444	SCV001943355	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-25	reviewed by expert panel	curation	The c.1A>G (p.Met1Val) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one proband meeting HDGC clinical criteria (PS4_supporting; SCV000760810.2). This variant was also found to co-segregate with disease in multiple affected family members (PP1; SCV000760810.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 3.1 as specified by the CDH1 Variant Curation Expert Panel: PVS1, PS4_supporting, PM2_supporting, PP1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639240	SCV000760810	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-31	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 532457). Disruption of the initiator codon has been observed in individuals with a personal or family history of diffuse gastric cancer and/or lobular breast cancer (PMID: 16061854, 20373070, 28202063; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change affects the initiator methionine of the CDH1 mRNA. The next in-frame methionine is located at codon 246.
Mendelics	RCV000639240	SCV001140125	pathogenic	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002420724	SCV002717796	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-13	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the CDH1 gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Though this exact mutation has not been reported in the literature, other initiation codon alterations (c.2T>C and c.3G>A) have been reported in multiple individuals with diffuse gastric cancer and/or lobular breast cancer (Pandalai PK et al. Surgery, 2011 Mar;149:347-55; Jalkh N et al. BMC Med Genomics, 2017 Feb;10:8; Hansford S et al. JAMA Oncol 2015 Apr;1(1):23-32; Guilford P et al. Gastric Cancer 2010 Mar; 13(1):1-10; Ambry internal data). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV000639240	SCV004044999	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation.