Submissions for variant NM_004360.5(CDH1):c.1565C>T (p.Thr522Ile)

dbSNP: rs863224725

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328263	SCV004035099	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-03	reviewed by expert panel	curation	The NM_004360.5(CDH1): c.1565C>T (p.Thr522Ile) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant was observed in the homozygous state in 1 individual without personal and/or family history of DGC, LBC, or SRC tumors (BP2_strong; internal laboratory contributors). This variant is known in one family with HDGC criteria (ERN_GENTURIS). In summary, the clinical significance of this variant is classified as benign based on BS2 and BP2_strong. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2, BP2_strong. (CDH1 VCEP specifications version 3.1; 06/26/2023)
Invitae	RCV000197897	SCV000254813	benign	Hereditary diffuse gastric adenocarcinoma	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000590454	SCV000279344	likely benign	not provided	2021-05-12	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with oral clefts, ichthyosis vulgaris or atopic dermatitis (Taylan 2015, Ittiwat 2016); This variant is associated with the following publications: (PMID: 31638429, 30287823, 19593635, 25819062, 27227907, 29641532)
Counsyl	RCV000197897	SCV000488402	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-03-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000448662	SCV000537599	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-30	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 522 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 2/251328 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.
Ambry Genetics	RCV000448662	SCV000661630	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	The p.T522I variant (also known as c.1565C>T), located in coding exon 10 of the CDH1 gene, results from a C to T substitution at nucleotide position 1565. The amino acid change results in threonine to isoleucine at codon 522, an amino acid with similar properties. This alteration was observed in with an allele frequency of 0.00009 in 11241 female controls and was not observed in 7051 unselected female breast cancer patients of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174680	SCV001337913	uncertain significance	not specified	2023-03-14	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1565C>T (p.Thr522Ile) results in a non-conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.4e-05 in 276562 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1565C>T has been reported in the literature in an individual affected with nonsyndromic oral clefts (Ittiwu_2016) and an individual affected with ichthyosis vulgaris and atopic dermatitis (Taylan_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or likely benign/benign (n=2). 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	RCV000197897	SCV003926811	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PS4_Supporting; PM2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000197897	SCV004019537	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-03	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.