Submissions for variant NM_004360.5(CDH1):c.2053G>A (p.Val685Met)

gnomAD frequency: 0.00001  dbSNP: rs550612843

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328186	SCV001365434	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The NM_004360.5(CDH1):c.2053G>A (p.Val685Met) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000665065.2, SCV000278915.9, SCV000260925.4). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Invitae	RCV000206023	SCV000260925	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000656822	SCV000278915	likely benign	not provided	2020-11-06	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 29936259, 26926684)
Ambry Genetics	RCV000574058	SCV000665065	likely benign	Hereditary cancer-predisposing syndrome	2020-11-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000574058	SCV000911484	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 685 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over ten individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest hereditary diffuse gastric cancer syndrome (ClinVar SCV001365434.1). This variant has been identified in 4/251468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120501	SCV001339070	uncertain significance	not specified	2020-03-20	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2053G>A (p.Val685Met) results in a conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251468 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2053G>A in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000574058	SCV002529103	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-06	criteria provided, single submitter	curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000206023	SCV003926884	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2 (PMID: 30311375)
ITMI	RCV000120501	SCV000084654	not provided	not specified	2013-09-19	no assertion provided	reference population