Submissions for variant NM_004360.5(CDH1):c.2076_2077inv (p.Gly693Ser)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328267	SCV001943363	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.2076_2077inv (p.Gly693Ser) variant has been observed in >10 (41) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000260738.9). 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205531	SCV000260738	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000773194	SCV000906767	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 693 of the CDH1 protein. This variant is also known as c.2076_2077delinsCA. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with thyroid cancer with positive family history of thyroid and breast cancer (PMID: 26699384). This variant has been identified in 12/282770 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.
GeneDx	RCV001260225	SCV001430926	uncertain significance	not provided	2020-08-18	criteria provided, single submitter	clinical testing	Located in the critical cadherin 5 extracellular domain (Brooks-Wilson 2004, Figueiredo 2013) In silico analysis supports that this variant does not alter protein structure/function Has not been previously published as pathogenic or benign to our knowledge Observed in 0.0042% (12/282770 alleles) in large population cohorts (Lek 2016)
Genetic Services Laboratory, University of Chicago	RCV001818500	SCV002070701	uncertain significance	not specified	2019-04-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000773194	SCV002727733	likely benign	Hereditary cancer-predisposing syndrome	2022-05-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.