Submissions for variant NM_004360.5(CDH1):c.79C>T (p.Pro27Ser)

gnomAD frequency: 0.00001  dbSNP: rs878854696

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328310	SCV000864597	uncertain significance	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-21	reviewed by expert panel	curation	The c.79C>T (p.Pro27Ser) variant has allele frequency <1 out of 100, 000 in the gnomAD cohort (1/156646 in gnomAD v2.1.1; PM2_Supporting). No additional evidence met criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226798	SCV000288496	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 27 of the CDH1 protein (p.Pro27Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with gastric cancer and/or breast cancer (PMID: 26182300, 35264596). ClinVar contains an entry for this variant (Variation ID: 239913). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000582299	SCV000689566	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 27 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 HDGC-associated cancer and in a related unaffected individual (PMID: 26182300). This variant has been identified in 1/156646 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.
PreventionGenetics, part of Exact Sciences	RCV000679582	SCV000806682	uncertain significance	not provided	2017-11-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000226798	SCV000839073	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000679582	SCV002099558	uncertain significance	not provided	2022-02-25	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: 26182300, 27720647)
Ambry Genetics	RCV000582299	SCV002678650	likely benign	Hereditary cancer-predisposing syndrome	2024-09-21	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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000226798	SCV003926926	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2 (PMID: 30311375)
Baylor Genetics	RCV004567743	SCV005060065	uncertain significance	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing