Submissions for variant NM_004360.5(CDH1):c.1585A>G (p.Thr529Ala)

dbSNP: rs776890776

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328268	SCV004035092	uncertain significance	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-02	reviewed by expert panel	curation	The c.1585A>G (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Thr by Ala at amino acid 529 (p.Thr529Ala). This variant has been observed in more than 3 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; PMID: 30287823, Ambry, Invitae). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203686	SCV000260983	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-05-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 529 of the CDH1 protein (p.Thr529Ala). This variant is present in population databases (rs776890776, gnomAD 0.04%). This missense change has been observed in individual(s) with diffuse gastric cancer (PMID: 32426482). ClinVar contains an entry for this variant (Variation ID: 220445). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine 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.
Ambry Genetics	RCV000562109	SCV000675990	likely benign	Hereditary cancer-predisposing syndrome	2017-08-31	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.
Counsyl	RCV000203686	SCV000785502	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-11-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000562109	SCV000908743	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 529 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 hereditary cancer in the literature. This variant has been identified in 6/251482 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.
Myriad Genetics, Inc.	RCV000203686	SCV004019570	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.
Fulgent Genetics, Fulgent Genetics	RCV005016568	SCV005644348	uncertain significance	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian cancer	2024-06-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355093	SCV001549868	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Thr529Ala variant was not identified in the literature nor was it identified in the COSMIC, MutDB, Insight Colon Cancer Gene Variant Database, or the Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs776890776) as “With Uncertain significance allele”, and in ClinVar and Clinvitae (1x classified as uncertain significance by Invitae in a case of hereditary diffuse gastric cancer). The variant was identified in control databases in 7 of 246262 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 7 of 17248 chromosomes (freq: 0.0004); it was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Thr529Ala residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to 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, HumanSpliceFinder) 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.