chr16-68819398-A-G
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4_ModerateBP6_Very_Strong
The NM_004360.5(CDH1):c.1684A>G(p.Thr562Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T562P) has been classified as Uncertain significance.
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.1684A>G | p.Thr562Ala | missense_variant | 11/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1501A>G | p.Thr501Ala | missense_variant | 10/15 | ||
CDH1 | NM_001317185.2 | c.136A>G | p.Thr46Ala | missense_variant | 11/16 | ||
CDH1 | NM_001317186.2 | c.-254-2603A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1684A>G | p.Thr562Ala | missense_variant | 11/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.264-3739T>C | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251490Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461504Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727044
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 11, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 06, 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 | Jan 27, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 25, 2017 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 28, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 25, 2019 | 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. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 26, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2018 | - - |
CDH1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 30, 2023 | The CDH1 c.1684A>G variant is predicted to result in the amino acid substitution p.Thr562Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68853301-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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 03, 2023 | The NM_004360.5(CDH1):c.1684A>G (p.Thr562Ala) 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). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at