16-68801774-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The ENST00000261769.10(CDH1):c.268C>T(p.Arg90Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90Q) has been classified as Likely benign.
Frequency
Consequence
ENST00000261769.10 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.268C>T | p.Arg90Trp | missense_variant | 3/16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.268C>T | p.Arg90Trp | missense_variant | 3/15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.-1348C>T | 5_prime_UTR_variant | 3/16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-1552C>T | 5_prime_UTR_variant | 3/15 | NP_001304115.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.268C>T | p.Arg90Trp | missense_variant | 3/16 | 1 | NM_004360.5 | ENSP00000261769 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251338Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135838
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461806Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727202
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:3
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 90 of the CDH1 protein (p.Arg90Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with gastric cancer (PMID: 23555086). ClinVar contains an entry for this variant (Variation ID: 182390). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 08, 2016 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2023 | 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 | Oct 09, 2023 | This missense variant replaces arginine with tryptophan at codon 90 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with familial gastric cancer in the literature (PMID: 23555086). In a large breast cancer case-control study, this variant was identified in 4/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/251338 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 21, 2021 | Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal and family history of gastric cancer (Fang 2013); This variant is associated with the following publications: (PMID: 24983367, 25925381, 23555086) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 29, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at