ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1849G>A (p.Ala617Thr) (rs33935154)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000013019 SCV000864628 benign Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.1849G>A (p.Ala617Thr) variant has an allele frequency of 0.04479 (4.5%, 1076/24,022 alleles) in the African subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BA1.
GeneDx RCV000120500 SCV000167597 benign not specified 2013-10-29 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.
Ambry Genetics RCV000130292 SCV000185140 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as 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.
Pathway Genomics RCV000013019 SCV000223773 benign Hereditary diffuse gastric cancer 2014-10-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120500 SCV000225610 benign not specified 2015-01-22 criteria provided, single submitter clinical testing
Invitae RCV000013019 SCV000261924 benign Hereditary diffuse gastric cancer 2020-12-04 criteria provided, single submitter clinical testing
Vantari Genetics RCV000130292 SCV000267032 benign Hereditary cancer-predisposing syndrome 2016-01-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000013019 SCV000398570 likely benign Hereditary diffuse gastric cancer 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Counsyl RCV000013019 SCV000488401 benign Hereditary diffuse gastric cancer 2016-03-23 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000130292 SCV000576454 likely benign Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130292 SCV000684383 benign Hereditary cancer-predisposing syndrome 2015-03-10 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120500 SCV000806645 benign not specified 2016-12-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282694 SCV000885159 benign none provided 2020-03-20 criteria provided, single submitter clinical testing
OMIM RCV000013018 SCV000033263 pathogenic Endometrial carcinoma 2003-03-01 no assertion criteria provided literature only
OMIM RCV000013019 SCV000033264 pathogenic Hereditary diffuse gastric cancer 2003-03-01 no assertion criteria provided literature only
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034706 SCV000043247 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000120500 SCV000084653 not provided not specified 2013-09-19 no assertion provided reference population
Mayo Clinic Laboratories, Mayo Clinic RCV000120500 SCV000691824 benign not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000130292 SCV000787978 benign Hereditary cancer-predisposing syndrome 2017-10-10 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356764 SCV001552021 benign Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 p.Ala617Thr variant was identified in 7 of 540 proband chromosomes (frequency: 0.013) from individuals or families with osteoblastic osteosarcoma, gastric adenocarcinoma, breast cancer and was present in 14 (all in African American) of 716 (516 African American) control chromosomes (frequency: 0.02) from healthy individuals (Choy 2012, El-Husny 2014, Suriano 2003, Valente 2014). The variant was also identified in dbSNP (ID: rs33935154) as With Pathogenic allele, ClinVar (classified as benign by GeneDx, Ambry Genetics, Pathway Genomics, Invitae, Vantari Genetics, Coulsyl; classified as pathogenic by OMIM), Clinvitae (conflicting interpretations of pathogenicity by ClinVar), Cosmic (neutral), databases. The variant was not identified in MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 1211(25 homozygous) of 277184 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1076 of 24022 chromosomes (freq: 0.045). The p.Ala617 residue is not conserved in mammals and four out of five 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. The variant is located with the Cadherin Cadherin-like functional domain increasing the liklihood that it may have clinical significance. Functional analysis by Suriano (2003) identified cells expressing the Ala617Thr mutation showed the same non-invasive behavior as cells expressing wild-type protein. The case study by Lajus (2015) found the variant in a family with no history of diffuse gastric cancer. The daughter diagnosed with in situ breast cancer does not carry the CDH1 mutation. The index case (72 year old) is alive without the evidence of breast or gastric cancer, and is on surveillance. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000120500 SCV001807351 benign not specified no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000120500 SCV001920376 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000120500 SCV001956047 benign not specified no assertion criteria provided clinical testing

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