ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1297G>A (p.Asp433Asn)

gnomAD frequency: 0.00007  dbSNP: rs199886166
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328168 SCV000864618 likely benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-17 reviewed by expert panel curation The c.1297G>A (p.Asp433Asn) 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). 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.
GeneDx RCV000588526 SCV000149747 uncertain significance not provided 2019-11-20 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast or gastric cancer (Schrader 2011, Li 2013, Tung 2016, Momozawa 2018); This variant is associated with the following publications: (PMID: 22722839, 30287823, 20921021, 23435907, 26976419, 26759166, 25096233, 26486520, 26182300)
Invitae RCV000123233 SCV000166539 likely benign Hereditary diffuse gastric adenocarcinoma 2024-01-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115838 SCV000183996 likely benign Hereditary cancer-predisposing syndrome 2018-10-12 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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 RCV000123233 SCV000488300 uncertain significance Hereditary diffuse gastric adenocarcinoma 2016-02-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588526 SCV000600955 likely benign not provided 2023-08-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235155 SCV000698358 likely benign not specified 2023-12-18 criteria provided, single submitter clinical testing Variant summary: CDH1 c.1297G>A (p.Asp433Asn) results in a conservative amino acid change located in the Cadherrin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 252334 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is benign. The variant has been reported in the literature in breast and gastric cancer patients, without strong evidence for causality (Schrader_2010, Tung_2016, Li_2013). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. One functional study reported the variant to have no impact on splicing, yielding normal-sized mRNA (Li_2013), however additional functional studies have not been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22722839, 20921021, 26976419, 23435907, 30287823, 28061482). 15 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=8) and VUS (n=7). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health RCV000115838 SCV000902710 likely benign Hereditary cancer-predisposing syndrome 2015-06-08 criteria provided, single submitter clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center RCV000123233 SCV001424030 uncertain significance Hereditary diffuse gastric adenocarcinoma 2018-06-21 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (G>A) that results in an aspartic acid to asparagine amino acid change at residue 433 in the CDH1 protein. The variant is rare, and is present in 3/120502 alleles (0.002%) in the ExAC database. The variant has been observed in a sporadic gastric cancer patient (PMID: 23435907) and at least two women with breast cancer, including one case of lobular breast cancer (PMID: 20921021) and one breast cancer of unspecified type (PMID: 26976419). This variant lies in cadherin repeat domain 3, but the aspartic acid at this position is not well conserved in this domain; several mammalian species have asparagine at this position. Additionally, the variant lies near a splice site, but mRNA analysis indicates no effects on proper splicing (PMID: 23435907). The majority of in silico tools queried predict that substituting asparagine for aspartic acid at this protein position will have a neutral effect on protein function. However, no functional tests to confirm these predictions have been performed, to our knowledge. At this time, we consider this to be a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000588526 SCV002049955 uncertain significance not provided 2020-11-10 criteria provided, single submitter clinical testing The CDH1 c.1297G>A; p.Asp433Asn variant (rs199886166) has been described in the literature in individuals with breast cancer without causality of the variant established (Momozawa 2018, Schrader 2011). The variant has been classified as likely benign by an expert panel in the ClinVar database but is also classified as a variant of uncertain significance by several sources (Variation ID: 127910). The variant is found in the general population with an overall allele frequency of 0.005% (13/251,484 alleles) in the Genome Aggregation Database. The aspartic acid at codon 433 is moderately conserved computational analyses predict that this variant is neutral (REVEL: 0.09). Due to limited information, the clinical significance of the p.Asp433Asn variant is uncertain at this time. References: Momozawa et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. Schrader et al. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet. 2011 Jan;48(1):64-8.
Sema4, Sema4 RCV000115838 SCV002529053 benign Hereditary cancer-predisposing syndrome 2020-07-21 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000235155 SCV002551771 likely benign not specified 2023-08-15 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 RCV000123233 SCV003926766 likely benign Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing BS2 (PMID: 30311375)
Myriad Genetics, Inc. RCV000123233 SCV004020036 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-03-07 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.
CeGaT Center for Human Genetics Tuebingen RCV000588526 SCV004140029 likely benign not provided 2022-10-01 criteria provided, single submitter clinical testing CDH1: BP4
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000123233 SCV000493723 uncertain significance Hereditary diffuse gastric adenocarcinoma 2015-09-26 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000588526 SCV001553149 uncertain significance not provided no assertion criteria provided clinical testing The CDH1 p.Asp433Asn variant was identified in 4 of 2232 proband chromosomes (frequency: 0.002) from individuals or families with lobular breast carcinoma, metanephric adenoma or gastric cancer and was not identified in 850 control chromosomes from healthy individuals (Ding 2018, Li 2013, Schrader 2011, Tung 2016). The variant was also identified in dbSNP (ID: rs199886166) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and four other submitters). The variant was identified in control databases in 12 of 246262 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 111710 chromosomes (freq: 0.00002), Ashkenazi Jewish in 8 of 9850 chromosomes (freq: 0.0008), and East Asian in 2 of 17248 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Finnish, and South Asian populations. RNA analysis of the p.Asp433Asn variant demonstrated normal-length mRNA, suggesting this variant does not induce splicing defects in E-cadherin (Li 2013). The p.Asp433 residue is not conserved in mammals and 5 of 5 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) 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.

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