rs121964871
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. BS2PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.2131C>G variant is <1/50,000 alleles (0.002%, 2/128,916 alleles) in the non-Finnish European subpopulation (PM2_Supporting; http://gnomad.broadinstitute.org). The 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). Use of the Bayesian point system for this variant with conflicting evidence. Therefore, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121988/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2131C>G | p.Leu711Val | missense_variant | 13/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1948C>G | p.Leu650Val | missense_variant | 12/15 | ||
CDH1 | NM_001317185.2 | c.583C>G | p.Leu195Val | missense_variant | 13/16 | ||
CDH1 | NM_001317186.2 | c.166C>G | p.Leu56Val | missense_variant | 12/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2131C>G | p.Leu711Val | missense_variant | 13/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250252Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135340
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461066Hom.: 0 Cov.: 34 AF XY: 0.0000316 AC XY: 23AN XY: 726856
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74306
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 07, 2023 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 11, 2017 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2018 | This variant is denoted CDH1 c.2131C>G at the cDNA level, p.Leu711Val (L711V) at the protein level, and results in the change of a Leucine to a Valine (CTG>GTG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been published as a somatic variant in an endometrial carcinoma with no evidence of tumoral loss of heterozygosity (Risinger 1994). CDH1 Leu711Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Transmembrane domain (Brooks-Wilson 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDH1 Leu711Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 01, 2022 | BP6, PM2_supporting - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 16, 2021 | This alteration is classified as likely 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 07, 2023 | This missense variant replaces leucine with valine at codon 711 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. A gastric cancer case-control study reported this variant in 41/359 cases and 25/368 controls (PMID: 28352678). This variant has been observed in over ten individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not meet hereditary diffuse gastric cancer syndrome (ClinVar: SCV001142276.2; Color internal data). This variant has been identified in 2/281652 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Endometrial carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1994 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 18, 2018 | - - |
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.Leu711Val variant was identified in the heterozygous or homozygous state in 41 of 359 Chinese probands with gastric cancer and in 25 of 368 healthy individuals, although the allele frequencies could not be calculated for either population as the frequencies of heterozygotes and homozygotes were not provided separately (Lin 2014). This variant has also been reported somatically in an endometrial carcinoma with no evidence of loss of heterozygosity in tumour tissue (Risinger 1994). The variant was identified in dbSNP (ID: rs121964871) as “With Pathogenic allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, Color and Counsyl). The variant was identified in control databases in 2 of 276082 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 126488 chromosomes (freq: 0.000016), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu711 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 18, 2023 | The c.2131C>G variant is <1/50,000 alleles (0.002%, 2/128,916 alleles) in the non-Finnish European subpopulation (PM2_Supporting; http://gnomad.broadinstitute.org). The 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). Use of the Bayesian point system for this variant with conflicting evidence. Therefore, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at