Submissions for variant NM_004360.5(CDH1):c.1244T>C (p.Ile415Thr)

gnomAD frequency: 0.00004  dbSNP: rs587782372

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131355	SCV000186331	likely benign	Hereditary cancer-predisposing syndrome	2022-06-23	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.
Invitae	RCV000462419	SCV000545374	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 415 of the CDH1 protein (p.Ile415Thr). This variant is present in population databases (rs587782372, gnomAD 0.008%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 142306). 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.
Color Diagnostics, LLC DBA Color Health	RCV000131355	SCV000684345	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-03	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 415 of the CDH1 protein. Computational prediction 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 performed for this variant. This variant has been reported in an individual affected with colorectal cancer in the literature (PMID 28135145). This variant has been identified in 2/282890 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759725	SCV000889243	uncertain significance	not provided	2018-06-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251339	SCV001426902	uncertain significance	not specified	2023-05-01	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1244T>C (p.Ile415Thr) results in a non-conservative amino acid change located in the third cadherin-like repeat domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251488 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1244T>C has been reported in the literature in at-least one individual affected with colorectal cancer (Yurgelun_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28135145). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=4), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000759725	SCV003805502	uncertain significance	not provided	2023-02-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in at least one individual with a personal history of colon cancer who underwent multi-gene panel testing (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 26489445, 15235021, 22850631, 28135145)
Baylor Genetics	RCV004567133	SCV005060073	uncertain significance	Familial cancer of breast	2024-02-24	criteria provided, single submitter	clinical testing