rs587781701
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The ENST00000261769.10(CDH1):c.2017C>A(p.Gln673Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. Q673H) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000261769.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2017C>A | p.Gln673Lys | missense_variant | 13/16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.1834C>A | p.Gln612Lys | missense_variant | 12/15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.469C>A | p.Gln157Lys | missense_variant | 13/16 | NP_001304114.1 | ||
CDH1 | NM_001317186.2 | c.52C>A | p.Gln18Lys | missense_variant | 12/15 | NP_001304115.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2017C>A | p.Gln673Lys | missense_variant | 13/16 | 1 | NM_004360.5 | ENSP00000261769 | P1 | |
ENST00000563916.1 | n.48G>T | non_coding_transcript_exon_variant | 1/3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152032Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251476Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135910
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461848Hom.: 0 Cov.: 33 AF XY: 0.0000784 AC XY: 57AN XY: 727244
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152032Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74254
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal or family history of breast cancer (Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 15235021, 22850631, 36436516) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 24, 2020 | - - |
Hereditary diffuse gastric adenocarcinoma Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto | Aug 01, 2022 | Not applicable criteria (PMID: 30311375) - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 07, 2022 | This missense variant replaces glutamine with lysine at codon 673 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 CDH1-related disorders in the literature. This variant has been identified in 7/251476 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 | Nov 15, 2021 | 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 specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 23, 2024 | Variant summary: CDH1 c.2017C>A (p.Gln673Lys) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2017C>A in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. c.2017C>A was detected in 2/9884 individuals in the FLOSSIES database (women older than age 70 without cancer). ClinVar contains an entry for this variant (Variation ID: 141376). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 20, 2021 | - - |
CDH1-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 16, 2024 | The CDH1 c.2017C>A variant is predicted to result in the amino acid substitution p.Gln673Lys. This variant has been reported in the literature in an individual with a family history of breast cancer (Garcia-Pelaez J et al. 2022. PubMed ID: 36436516). This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141376/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at