Submissions for variant NM_004360.5(CDH1):c.344C>T (p.Thr115Met)

gnomAD frequency: 0.00002  dbSNP: rs370973869

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328206	SCV004035098	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-03	reviewed by expert panel	curation	The c.344C>T (p.Thr115Met) missense variant has a maximum subpopulation frequency of 0.0097% in the gnomAD v2.1.1 cohort (http://gnomad.broadinstitute.org). This variant has been observed in over 75 probands not meeting HDGC phenotype criteria (BS2; SCV000254830.11, SCV000210896.16, SCV000183817.7). In summary, this variant meets criteria to be classified as Likely Benign based on the 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	RCV000129106	SCV000183817	likely benign	Hereditary cancer-predisposing syndrome	2020-09-02	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.
GeneDx	RCV000212350	SCV000210896	uncertain significance	not provided	2022-08-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals undergoing hereditary cancer testing but also present in controls (Momozawa et al., 2018; Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 15235021, 30287823, 31159747)
Invitae	RCV000197330	SCV000254830	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129106	SCV000684456	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 115 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 29522266) but also in control individuals (PMID: 30287823). This variant has been identified in 7/282510 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.
Counsyl	RCV000197330	SCV000785151	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-05-08	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000129106	SCV000821976	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000197330	SCV004020010	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.
Baylor Genetics	RCV003460887	SCV004215600	uncertain significance	Familial cancer of breast	2023-10-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212350	SCV004220829	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000047 (6/128864 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been identified in women affected with breast cancer (PMID: 29522266 (2018), 34130653 (2021)) or at-risk of breast/ovarian cancer (PMID: 31159747 (2019), 34359559 (2021)). It was also identified only in the control groups for studies of biliary tract cancer (PMID: 36243179 (2022)), breast cancer (PMID: 30287823 (2018)), pancreatic cancer (PMID: 32980694 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.