Submissions for variant NM_004360.5(CDH1):c.1684A>G (p.Thr562Ala)

gnomAD frequency: 0.00002  dbSNP: rs587782061

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328216	SCV004035103	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-03	reviewed by expert panel	curation	The NM_004360.5(CDH1):c.1684A>G (p.Thr562Ala) 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; internal laboratory contributors). 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: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023)
Ambry Genetics	RCV000130539	SCV000185408	likely benign	Hereditary cancer-predisposing syndrome	2019-03-25	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233909	SCV000288444	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000233909	SCV000488384	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-03-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001283957	SCV000517007	likely benign	not provided	2018-11-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130539	SCV000689476	likely benign	Hereditary cancer-predisposing syndrome	2017-05-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283957	SCV001469486	uncertain significance	not provided	2023-12-18	criteria provided, single submitter	clinical testing	The CDH1 c.1684A>G (p.Thr562Ala) variant has been reported in the published literature in an individual with acute lymphoblastic leukemia (ALL) (PMID: 26580448 (2015)), and in an individual with breast cancer as well as in a reportedly healthy individual in a breast cancer association study (PMID: 33471991 (2021)). This variant was found to co-occur with a pathogenic variant in BRCA2 in one individual (Quest internal data). The frequency of this variant in the general population, 0.000012 (3/251490 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on CDH1 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000130539	SCV002529084	likely benign	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000233909	SCV004019593	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-06	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV003390820	SCV004119104	uncertain significance	CDH1-related disorder	2023-05-30	criteria provided, single submitter	clinical testing	The CDH1 c.1684A>G variant is predicted to result in the amino acid substitution p.Thr562Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68853301-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.