Submissions for variant NM_004360.5(CDH1):c.2351G>A (p.Arg784His)

gnomAD frequency: 0.00001  dbSNP: rs763203357

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204130	SCV000260692	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 784 of the CDH1 protein (p.Arg784His). This variant is present in population databases (rs763203357, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer or nonsyndromic cleft lip with or without cleft palate, that had no family history of cancer (PMID: 26123647, 35264596). ClinVar contains an entry for this variant (Variation ID: 220271). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDH1 function (PMID: 26123647). 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.
GeneDx	RCV000481744	SCV000567397	uncertain significance	not provided	2019-11-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate no damaging effect: normal protein expression, cellular localization, adhesion, and invasive ability in vitro (Brito 2015); Observed to segregate with disease in a family with nonsyndromic cleft lip and palate (Brito 2015); This variant is associated with the following publications: (PMID: 26123647, 29348693, 25801821, 31638429, 30661051)
Ambry Genetics	RCV000563859	SCV000668985	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	The p.R784H variant (also known as c.2351G>A), located in coding exon 15 of the CDH1 gene, results from a G to A substitution at nucleotide position 2351. The arginine at codon 784 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in a proband with nonsyndromic cleft lip and palate, as well as three other affected relatives with nonsyndromic cleft lip with or without cleft palate; however, this alteration was not present in one relative with a submucosal cleft palate, and there were no reported cancer diagnoses in the family (Brito LA et al. Hum Mutat. 2015 Nov;36:1029-33). This alteration was also detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics	RCV000204130	SCV000839096	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-07-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417744	SCV004117433	uncertain significance	CDH1-related disorder	2023-07-31	criteria provided, single submitter	clinical testing	The CDH1 c.2351G>A variant is predicted to result in the amino acid substitution p.Arg784His. To our knowledge, this variant has not been reported to be associated with cancer in the literature. However, this variant has been described in association with isolated cleft lip/palate in a single family without a history of cancer (Brito et al. 2015. PubMed ID: 26123647). However, functional studies found this variant does not impact CDH1 function (Brito et al. 2015. PubMed ID: 26123647). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68863612-G-A) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/220271/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Color Diagnostics, LLC DBA Color Health	RCV000563859	SCV004360526	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 784 of the CDH1 protein. Functional studies have demonstrated normal protein expression, plasma membrane localization, adhesive behavior, and invasive potential (PMID: 26123647). This variant has not been reported in individuals affected with hereditary cancer in the literature, but has been observed in several members of a family with Nonsyndromic cleft lip with or without cleft palate (NSCL/P; PMID: 26123647). This variant has been identified in 1/251462 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.