ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2512A>G (p.Ser838Gly) (rs121964872)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115857 SCV000183966 likely benign Hereditary cancer-predisposing syndrome 2017-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,In silico models in agreement (benign)
ClinGen CDH1 Variant Curation Expert Panel RCV000198450 SCV000864627 uncertain significance Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.2512A>G (p.Ser838Gly) 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). There is no other supporting data that meet criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2.
Color RCV000115857 SCV000910736 likely benign Hereditary cancer-predisposing syndrome 2015-12-16 criteria provided, single submitter clinical testing
Counsyl RCV000198450 SCV000487808 uncertain significance Hereditary diffuse gastric cancer 2015-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000212390 SCV000149766 likely benign not specified 2017-11-30 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
GeneKor MSA RCV000115857 SCV000821975 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212390 SCV000698387 uncertain significance not specified 2019-02-22 criteria provided, single submitter clinical testing CDH1 c.2512A>G (p.Ser838Gly) results in a non-conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 299726 control chromosomes (gnomAD and publication), predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6 fold of our internal estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast and Ovarian Cancer phenotype (2.1e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, this frequency does not exceed the allele frequency threshold of 0.001 set by the ClinGen CDH1 variant curation expert panel (Lee_2018). c.2512A>G has been reported in the literature in individuals affected with cancer, including breast cancer, Lynch syndrome-associated cancer and pancreatic neuroendocrine tumor (Hauke_2018, Shindo_2017, Tung_2015, Yurgelun_2015). In one study, the variant was detected in an unaffected female proband (45 years old) from a BRCA1-positive ( c.1016dupA, p.Val340fsX6) family with a history of breast and ovarian cancer (Stuebs_2018). Taken altogether, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Another co-occurrence with a pathogenic variant has been reported in our internal database (BRCA2 c.6025C>T, p.Gln2009X), providing supporting evidence for a benign role. Furthermore, the variant of interest was detected in 2 women in the FLOSSIES database older than age 70 years who have never had cancer, providing further supporting evidence for a benign role. Seven ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as uncertain significance (4x) and as likely benign (3x). Based on the evidence outlined above, although all evidence points to this variant being likely benign, to align with the CDH1-expert panel conclusion, the variant was classified as a VUS-possibly benign
Invitae RCV000198450 SCV000254825 uncertain significance Hereditary diffuse gastric cancer 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 838 of the CDH1 protein (p.Ser838Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs121964872, ExAC 0.006%). This variant has been reported in an individual with suspected Lynch syndrome, and an individual affected with breast and/or ovarian cancer (PMID: 25980754, 27616075). ClinVar contains an entry for this variant (Variation ID: 12233). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
OMIM RCV000013020 SCV000033265 pathogenic Neoplasm of ovary 1994-05-01 no assertion criteria provided literature only
University of Washington Department of Laboratory Medicine,University of Washington RCV000198450 SCV000788250 likely benign Hereditary diffuse gastric cancer 2018-05-26 criteria provided, single submitter research The CDH1 variant designated as NM_004360.3:c.2512A>G (p.Ser838Gly) is classified as likely benign in the context of hereditary diffuse gastric cancer syndrome (Hansford 2015, PMID:26182300). This variant was identified or imputed in several family members age 65 or older who have not had gastric cancer or lobular breast cancer. This variant is listed in population databases (rs121964872) and is found in approximately 1 out of 9000 individuals of European ancestry ( This variant is predicted to be tolerated by in silico prediction tools (SIFT, PolyPhen-2, Align-GVGD). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to cause hereditary diffuse gastric cancer syndrome. A smaller increase in cancer risk that the risk reported in the literature due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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