Submissions for variant NM_004360.5(CDH1):c.1454T>C (p.Ile485Thr)

dbSNP: rs587783049

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575121	SCV000669053	likely benign	Hereditary cancer-predisposing syndrome	2024-08-29	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.
Color Diagnostics, LLC DBA Color Health	RCV000575121	SCV000908815	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 485 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780088	SCV000917116	uncertain significance	not specified	2017-10-26	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.1454T>C (p.Ile485Thr) variant involves the alteration of a conserved nucleotide that lies within one of the cadherin domains (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 246266 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001319019	SCV001509743	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-04	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 485 of the CDH1 protein (p.Ile485Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian, uterine and thyroid cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 483253). 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 tolerated. 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.
GenomeConnect - Invitae Patient Insights Network	RCV001319019	SCV001749765	not provided	Hereditary diffuse gastric adenocarcinoma		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-24-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
GenomeConnect, ClinGen	RCV001319019	SCV002074995	not provided	Hereditary diffuse gastric adenocarcinoma		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-24-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.