Submissions for variant NM_004360.5(CDH1):c.1241C>A (p.Thr414Asn)

gnomAD frequency: 0.00006  dbSNP: rs755571454

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164120	SCV000214735	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	The p.T414N variant (also known as c.1241C>A), located in coding exon 9 of the CDH1 gene, results from a C to A substitution at nucleotide position 1241. The threonine at codon 414 is replaced by asparagine, an amino acid with similar properties. This alteration was identified in tumor testing of a colorectal signet-ring cell carcinoma and also suggested evidence of being germline (Aitchison A et al. Pathol Res Pract, 2020 May;216:152912). In another study, this alteration was identified in individuals with a personal and/or family history of breast cancer (Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466208	SCV000545426	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 414 of the CDH1 protein (p.Thr414Asn). This variant is present in population databases (rs755571454, gnomAD 0.02%). 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: 184801). 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.
GeneDx	RCV000590115	SCV000570214	uncertain significance	not provided	2023-11-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 32147272, 15235021, 22850631)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260252	SCV000698356	uncertain significance	not specified	2020-09-29	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1241C>A (p.Thr414Asn) results in a non-conservative amino acid change located in the Cadherin-like of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251490 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1241C>A has been reported in the literature, without strong evidence for causality (Aitchison_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000164120	SCV000906641	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-19	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 414 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset, colorectal signet-ring cell carcinoma (PMID: 32147272). This variant has been identified in 5/282882 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000466208	SCV002012423	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2021-08-19	criteria provided, single submitter	clinical testing	The CDH1 c.1241C>A (p.Thr414Asn) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 with a maximum of 4 alleles present in a subpopulation (https://gnomad.broadinstitute.org/variant/16-68847319-C-A). Guidelines for the classification of CDH1 germline variants recommend that BS1 is applied when 5 or more alleles are present in a subpopulation. Seven of seven in silico tools predict a benign effect of this variant on protein function, however these predictions have not been confirmed by functional assays. BP4 is not applied since in silico data is not recommended for use in CDH1 variant curation. To our knowledge, this variant has not been reported in individuals with hereditary diffuse gastric cancer. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the CDH1 Variant Curation Expert Panel (PMID: 30311375): no criteria met.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000466208	SCV003926761	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	Not applicable criteria (PMID: 30311375)
Baylor Genetics	RCV004567236	SCV005060125	uncertain significance	Familial cancer of breast	2023-12-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000466208	SCV001550789	uncertain significance	Hereditary diffuse gastric adenocarcinoma		no assertion criteria provided	clinical testing	The CDH1 p.Thr414Asn variant was not identified in the literature. The variant was identified in dbSNP (ID: rs755571454) “With Uncertain significance allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 6 of 277224 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 4 of 24032 chromosomes (freq: 0.0002), Other in 1 of 6466 chromosomes (freq: 0.0002) and Latino in 1 of 34420 chromosomes (freq: 0.00003), while it was not observed in the European, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The p.Thr414 residue falls within the cadherin-like protein domain and is not conserved in mammals; computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Asn variant impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.