Submissions for variant NM_004360.5(CDH1):c.269G>A (p.Arg90Gln)

gnomAD frequency: 0.00002  dbSNP: rs587782647

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328231	SCV001943361	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.269G>A (p.Arg90Gln) missense variant has a frequency of 0.00001989 (5 of 251,334) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00004401 (5 of 113,622) in the European non-Finnish subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in at least 10 (55) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000567761.3, SCV000254829.7). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Ambry Genetics	RCV000132054	SCV000187116	likely benign	Hereditary cancer-predisposing syndrome	2018-09-14	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	RCV000200245	SCV000254829	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-12-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000482830	SCV000567761	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with a personal or family history of breast cancer (Guindalini et al., 2022; Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 24030381, 25344691, 28229982, 30287823, 32175104, 15235021, 35264596, 36436516)
Color Diagnostics, LLC DBA Color Health	RCV000132054	SCV000689524	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 90 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 5/251334 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.
Counsyl	RCV000200245	SCV000784796	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-12-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000200245	SCV000839075	benign	Hereditary diffuse gastric adenocarcinoma	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482830	SCV002046545	uncertain significance	not provided	2020-12-30	criteria provided, single submitter	clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000200245	SCV003927011	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000200245	SCV004020009	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-06	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.