rs201141645
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2BS1
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA163740/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.546A>C | p.Lys182Asn | missense_variant | 5/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.546A>C | p.Lys182Asn | missense_variant | 5/15 | ||
CDH1 | NM_001317185.2 | c.-1070A>C | 5_prime_UTR_variant | 5/16 | |||
CDH1 | NM_001317186.2 | c.-1274A>C | 5_prime_UTR_variant | 5/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.546A>C | p.Lys182Asn | missense_variant | 5/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000796 AC: 20AN: 251196Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135770
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 727234
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74486
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 04, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 25, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2021 | This alteration is classified as 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. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 03, 2022 | 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. - |
Hereditary diffuse gastric adenocarcinoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2021 | 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) - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
Benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 10, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at