rs1555515297

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PVS1_StrongBS2_SupportingPM5_SupportingPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.687+2T>C variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant is at +2 donor site variant with other likely pathogenic canonical splicing variants curated at the same splice site (PM5_Supporting). The variant has been observed in 6 individuals without DGC, SRC tumors or LBC and whose families do not suggest HDGC (BS2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PM5_Supporting, BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA396458165/MONDO:0007648/007

Frequency

Genomes: not found (cov: 32)

Consequence

CDH1
NM_004360.5 splice_donor, intron

Scores

4
2
1
Splicing: ADA: 0.9845
1
1

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:1

Conservation

PhyloP100: 7.46
Variant links:
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
BS2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH1NM_004360.5 linkuse as main transcriptc.687+2T>C splice_donor_variant, intron_variant ENST00000261769.10 NP_004351.1 P12830-1A0A0U2ZQU7B3GN61
CDH1NM_001317184.2 linkuse as main transcriptc.687+2T>C splice_donor_variant, intron_variant NP_001304113.1 P12830-2B3GN61
CDH1NM_001317185.2 linkuse as main transcriptc.-929+2T>C splice_donor_variant, intron_variant NP_001304114.1 P12830B3GN61Q9UII7
CDH1NM_001317186.2 linkuse as main transcriptc.-1133+2T>C splice_donor_variant, intron_variant NP_001304115.1 P12830B3GN61

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.687+2T>C splice_donor_variant, intron_variant 1 NM_004360.5 ENSP00000261769.4 P12830-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 28, 2022For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 463790). Disruption of this splice site has been observed in individuals with diffuse gastric cancer (PMID: 15235021; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). -
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 07, 2019The c.687+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 5 in the CDH1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the ESEfinder and HSF splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -
CDH1-related diffuse gastric and lobular breast cancer syndrome Uncertain:1
Uncertain significance, reviewed by expert panelcurationClinGen CDH1 Variant Curation Expert PanelFeb 26, 2024The c.687+2T>C variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant is at +2 donor site variant with other likely pathogenic canonical splicing variants curated at the same splice site (PM5_Supporting). The variant has been observed in 6 individuals without DGC, SRC tumors or LBC and whose families do not suggest HDGC (BS2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PM5_Supporting, BS2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Pathogenic
29
DANN
Uncertain
0.98
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Benign
0.67
SpliceAI score (max)
0.54
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.54
Position offset: -44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555515297; hg19: chr16-68842753; API