Submissions for variant NM_004360.5(CDH1):c.1132A>C (p.Thr378Pro)

gnomAD frequency: 0.00001  dbSNP: rs587781432

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129325	SCV000184088	likely benign	Hereditary cancer-predisposing syndrome	2022-07-11	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.
Invitae	RCV000526444	SCV000637698	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759721	SCV000889237	likely benign	not provided	2023-08-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129325	SCV001358491	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 378 of the CDH1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 3 individuals affected with breast cancer and 1 unaffected individual (PMID: 31206626). This variant has been identified in 10/251474 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	RCV000759721	SCV001801305	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 15235021, 22850631)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804851	SCV002051387	likely benign	not specified	2021-12-27	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1132A>C (p.Thr378Pro) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251474 control chromosomes. The observed variant frequency is approximately 1.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Breast Cancer phenotype (2.1e-05), strongly suggesting that the variant is benign. c.1132A>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with Breast Cancer as well as in unaffected controls (example, Weitzel_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast and/or Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 likely benign.