Submissions for variant NM_004360.5(CDH1):c.1610C>T (p.Pro537Leu)

gnomAD frequency: 0.00002  dbSNP: rs730881667

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212373	SCV000210917	uncertain significance	not provided	2018-08-28	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.1610C>T at the cDNA level, p.Pro537Leu (P537L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. CDH1 Pro537Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the cadherin 4 domain (Brooks-Wilson 2004, Figueiredo 2013, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDH1 Pro537Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000160393	SCV000214508	likely benign	Hereditary cancer-predisposing syndrome	2023-06-05	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	RCV000234355	SCV000288441	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 537 of the CDH1 protein (p.Pro537Leu). This variant is present in population databases (rs730881667, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 182399). 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 disruptive. 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	RCV000160393	SCV000684369	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 537 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in one individual each of East Asian ancestry affected with diffuse gastric cancer at age 60 (PMID: 25583476) and breast cancer (PMID: 30287823). This variant also has been observed in unaffected control individuals of Japanese ancestry and has been identified in 4/18394 chromosomes in the East Asian population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in two individuals affected with gastric or breast cancer and in several individuals selected for the lack of breast cancer or found in the general East Asian population. 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	RCV000234355	SCV000786291	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-04-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000234355	SCV004019591	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.
Baylor Genetics	RCV004567205	SCV005060104	uncertain significance	Familial cancer of breast	2024-01-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000212373	SCV005193463	uncertain significance	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356277	SCV001551399	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The CDH1 p.Pro537Leu variant was not identified in the literature. The variant was identified in dbSNP (ID: rs730881667) as "With Uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, Color and Counsyl). The variant was identified in control databases in 7 of 246266 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111716 chromosomes (freq: 0.00003) and East Asian in 4 of 17248 chromosomes (freq: 0.0002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Pro537 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.