16-68819299-A-G
Variant summary
Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.1585A>G (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Thr by Ala at amino acid 529 (p.Thr529Ala). This variant has been observed in more than 3 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; PMID:30287823, Ambry, Invitae). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA347984/MONDO:0100488/007
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1585A>G | p.Thr529Ala | missense_variant | 11/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1402A>G | p.Thr468Ala | missense_variant | 10/15 | ||
CDH1 | NM_001317185.2 | c.37A>G | p.Thr13Ala | missense_variant | 11/16 | ||
CDH1 | NM_001317186.2 | c.-254-2702A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1585A>G | p.Thr529Ala | missense_variant | 11/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.264-3640T>C | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251482Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135916
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727240
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 03, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 14, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 529 of the CDH1 protein (p.Thr529Ala). This variant is present in population databases (rs776890776, gnomAD 0.04%). This missense change has been observed in individual(s) with diffuse gastric cancer (PMID: 32426482). ClinVar contains an entry for this variant (Variation ID: 220445). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 17, 2020 | This missense variant replaces threonine with alanine at codon 529 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/251482 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 31, 2017 | 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. - |
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 02, 2023 | The c.1585A>G (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Thr by Ala at amino acid 529 (p.Thr529Ala). This variant has been observed in more than 3 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; PMID: 30287823, Ambry, Invitae). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) - |
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.Thr529Ala variant was not identified in the literature nor was it identified in the COSMIC, MutDB, Insight Colon Cancer Gene Variant Database, or the Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs776890776) as “With Uncertain significance allele”, and in ClinVar and Clinvitae (1x classified as uncertain significance by Invitae in a case of hereditary diffuse gastric cancer). The variant was identified in control databases in 7 of 246262 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 7 of 17248 chromosomes (freq: 0.0004); it was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Thr529Ala 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at