Submissions for variant NM_004360.5(CDH1):c.2401C>G (p.Pro801Ala)

dbSNP: rs876660704

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217230	SCV000278342	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-28	criteria provided, single submitter	clinical testing	The p.P801A variant (also known as c.2401C>G), located in coding exon 15 of the CDH1 gene, results from a C to G substitution at nucleotide position 2401. The proline at codon 801 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796116	SCV000935613	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 801 of the CDH1 protein (p.Pro801Ala). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 233879). 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	RCV000217230	SCV001353596	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 801 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251398 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.
Baylor Genetics	RCV003463594	SCV004215672	uncertain significance	Familial cancer of breast	2023-08-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003897505	SCV004714288	uncertain significance	CDH1-related disorder	2024-02-02	no assertion criteria provided	clinical testing	The CDH1 c.2401C>G variant is predicted to result in the amino acid substitution p.Pro801Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD, indicating it is rare. This variant is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/233879/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.