chr16-68801883-C-T
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_004360.5(CDH1):c.377C>T(p.Pro126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. P126S) has been classified as Likely benign.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
Publications
- blepharocheilodontic syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
- CDH1-related diffuse gastric and lobular breast cancer syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- hereditary diffuse gastric adenocarcinomaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
- cleft soft palateInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- orofacial cleft 3Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- blepharocheilodontic syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.377C>T | p.Pro126Leu | missense_variant | Exon 3 of 16 | ENST00000261769.10 | NP_004351.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152196Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 250648 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461282Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 726990 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74334 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:3Benign:1
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. -
BS2_Supporting (PMID: 30311375) -
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
not provided Uncertain:3
The CDH1 c.377C>T (p.Pro126Leu) variant has been reported in the published literature in an individual with breast cancer (PMID: 31871109 (2019)), and in another individual with colorectal cancer who also carried a pathogenic variant in the MSH2 gene (PMID: 28640387 (2017)). In a breast cancer association study, this variant was observed in a reportedly healthy individual (PMID: 33471991 (2021), see LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000098 (3/30610 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer who also carried a pathogenic variant in MSH2 (Ricker 2017); This variant is associated with the following publications: (PMID: 31871109, 28640387) -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
This missense variant replaces proline with leucine at codon 126 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 31871109) and colorectal cancer (PMID: 28640387). In a large breast cancer case-control study, this variant has been reported in 0/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 9/282034 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. -
Familial cancer of breast;C0376358:Prostate cancer;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Uncertain:1
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Ovarian cancer;C1708349:Hereditary diffuse gastric adenocarcinoma Uncertain:1
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Hereditary breast ovarian cancer syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at