Submissions for variant NM_004360.5(CDH1):c.200C>G (p.Ala67Gly)

dbSNP: rs730881660

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160381	SCV000210892	uncertain significance	not provided	2020-02-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458777	SCV000545465	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 67 of the CDH1 protein (p.Ala67Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182389). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001014024	SCV001174681	benign	Hereditary cancer-predisposing syndrome	2024-02-29	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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	RCV001014024	SCV001353740	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 67 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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	RCV001192626	SCV001360876	uncertain significance	not specified	2019-01-29	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.200C>G (p.Ala67Gly) results in a non-conservative amino acid change located in the cadherin prodomain (IPR014868) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246208 control chromosomes (gnomAD). 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.200C>G in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003462087	SCV004215634	uncertain significance	Familial cancer of breast	2023-09-28	criteria provided, single submitter	clinical testing