Submissions for variant NM_004360.5(CDH1):c.546A>C (p.Lys182Asn)

gnomAD frequency: 0.00001  dbSNP: rs201141645

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328203	SCV001943335	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.546A>C (p.Lys182Asn) variant has an allele frequency of 0.00104 (>0.1%, 9 out of 8628 alleles) in the East Asian subpopulation of the ExAC cohort (BS1). The variant has also been observed in >10 (56) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000637839.5; SCV000566004.5). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2.
Ambry Genetics	RCV000129061	SCV000183762	benign	Hereditary cancer-predisposing syndrome	2021-11-05	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.
GeneDx	RCV000485548	SCV000566004	likely benign	not provided	2021-01-19	criteria provided, single submitter	clinical testing	Observed in individuals with diffuse gastric cancer (Cho 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in 0.008% (20/251196 alleles) in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28522256, 31159747, 32426482, 33309985, 32241597)
Invitae	RCV001081944	SCV000637839	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-29	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000129061	SCV000821978	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129061	SCV000903227	benign	Hereditary cancer-predisposing syndrome	2016-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844046	SCV002103745	benign	not specified	2022-02-03	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.546A>C (p.Lys182Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251196 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 39 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Breast Cancer phenotype (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.546A>C in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign n=2, likely benign n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000129061	SCV002529193	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354143	SCV001548685	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Lys182Asn variant was not reported in the literature as identified in an affected population. The variant was identified in dbSNP (ID: rs201141645 as "With Likely benign, Uncertain significance allele") and ClinVar (3x as uncertain significance by Ambry Genetics, GeneDx, and Invitae). The variant was not identified in Cosmic, MutDB, or Zhejiang University databases. The variant was identified in control databases in 21 of 276982 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 15 of 18866 chromosomes (freq: 0.0008), Other in 1 of 6466 chromosomes (freq: 0.0002), European in 1 of 126514 chromosomes (freq: 0.000008), and South Asian in 4 of 30780 chromosomes (freq: 0.0001), while the variant was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. One aggregation assay showed that the Lys182Asn variant behaved similarly to the wildtype protein in CHO cells (Cho 2017). The p.Lys182 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 only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.