Submissions for variant NM_004360.5(CDH1):c.1149G>C (p.Gln383His)

gnomAD frequency: 0.00001  dbSNP: rs786202510

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165354	SCV000216079	likely benign	Hereditary cancer-predisposing syndrome	2022-04-08	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233683	SCV000288421	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 383 of the CDH1 protein (p.Gln383His). This variant is present in population databases (rs786202510, gnomAD 0.002%). This missense change has been observed in individual(s) with CDH1-related conditions (PMID: 36436516). ClinVar contains an entry for this variant (Variation ID: 185856). 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.
Color Diagnostics, LLC DBA Color Health	RCV000165354	SCV000537612	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 383 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 CDH1-related disorders in the literature. This variant has been identified in 2/251466 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.
GeneDx	RCV000484108	SCV000566708	uncertain significance	not provided	2022-11-21	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; Observed in an individual with breast, ovarian, or prostate cancer (Bishop et al., 2019); This variant is associated with the following publications: (PMID: 31415627, 15235021, 22850631, 32658311)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192622	SCV001360872	uncertain significance	not specified	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1149G>C (p.Gln383His) results in a non-conservative amino acid change located in the cadherin-like domain (IPR002126) of the encoded protein sequence. Four 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 252446 control chromosomes (gnomAD and Akcay_2021). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1149G>C has been reported in the literature as a VUS in an individual affected with Breast Cancer (Garcia-Pelaez_2022). This report does not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 36436516). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as uncertain significance and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000233683	SCV003926749	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2 (PMID: 30311375)