rs863224726
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_SupportingPS4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.1613A>T (p.Asp538Val) variant is absent in the gnomAD cohort (PM2_Supporting). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; SCV000254814.3). In summary, this variant meets criteria to be classified as a variant of uncertain significance based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA338255/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1613A>T | p.Asp538Val | missense_variant | 11/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1430A>T | p.Asp477Val | missense_variant | 10/15 | ||
CDH1 | NM_001317185.2 | c.65A>T | p.Asp22Val | missense_variant | 11/16 | ||
CDH1 | NM_001317186.2 | c.-254-2674A>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1613A>T | p.Asp538Val | missense_variant | 11/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.264-3668T>A | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 216589). This missense change has been observed in individuals with clinical features of hereditary diffuse gastric and lobular breast cancer syndrome (Invitae; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 538 of the CDH1 protein (p.Asp538Val). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2022 | The c.1613A>T variant (also known as p.D538V), located in coding exon 11 of the CDH1 gene, results from an A to T substitution at nucleotide position 1613. The aspartic acid at codon 538 is replaced by valine, an amino acid with highly dissimilar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with CDH1-related disease (Ambry internal data, personal communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 21, 2023 | The c.1613A>T (p.Asp538Val) variant is absent in the gnomAD cohort (PM2_Supporting). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; SCV000254814.3). In summary, this variant meets criteria to be classified as a variant of uncertain significance based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS4_Moderate. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at