rs1060501247
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_004360.5(CDH1):c.199G>A(p.Ala67Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A67D) has been classified as Uncertain significance.
Frequency
Consequence
NM_004360.5 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 | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.199G>A | p.Ala67Thr | missense_variant | 3/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.199G>A | p.Ala67Thr | missense_variant | 3/15 | ||
CDH1 | NM_001317185.2 | c.-1417G>A | 5_prime_UTR_variant | 3/16 | |||
CDH1 | NM_001317186.2 | c.-1621G>A | 5_prime_UTR_variant | 3/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.199G>A | p.Ala67Thr | missense_variant | 3/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251456Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135902
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727234
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 21, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 67 of the CDH1 protein (p.Ala67Thr). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 406667). 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 tolerated. 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 | 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 24, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 26, 2021 | This missense variant replaces alanine with threonine at codon 67 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 3/251456 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. - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2023 | This alteration is classified as 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. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at