rs777822181
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PM2_SupportingBS2BP4BP7
This summary comes from the ClinGen Evidence Repository: The c.270G>A variant (NM_004360.5) is a synonymous (silent) variant (p.Arg90=) that is not predicted by SpliceAI, varSEAK to impact splicing (BP4, BP7). This variant has been observed in more than 10 heterozygous individuals with no GC, DGC, SRC tumors and whose families do not suggest HDGC (BS2; Invitae, Ambry, GeneDX). The variant is 1 out of 251,334 alleles (less than 1 out of 100,000) in gnomAD 2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign for DGLBCS based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, BP4, BP7, PM2_Supporting. The CDH1 VCEP classified the variant with conflicting criteria to likely benign based on Bayesian points calculation. (CDH1 VCEP specifications version 3.1; 05/06/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8129820/MONDO:0100488/007
Frequency
Consequence
NM_004360.5 synonymous
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.270G>A | p.Arg90Arg | synonymous_variant | Exon 3 of 16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.270G>A | p.Arg90Arg | synonymous_variant | Exon 3 of 15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.-1346G>A | 5_prime_UTR_variant | Exon 3 of 16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-1550G>A | 5_prime_UTR_variant | Exon 3 of 15 | NP_001304115.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251334Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135838
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
- -
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. -
- -
Hereditary diffuse gastric adenocarcinoma Benign:2
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
- -
not specified Benign:1
- -
not provided Benign:1
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
The c.270G>A variant (NM_004360.5) is a synonymous (silent) variant (p.Arg90=) that is not predicted by SpliceAI, varSEAK to impact splicing (BP4, BP7). This variant has been observed in more than 10 heterozygous individuals with no GC, DGC, SRC tumors and whose families do not suggest HDGC (BS2; Invitae, Ambry, GeneDX). The variant is 1 out of 251,334 alleles (less than 1 out of 100,000) in gnomAD 2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign for DGLBCS based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, BP4, BP7, PM2_Supporting. The CDH1 VCEP classified the variant with conflicting criteria to likely benign based on Bayesian points calculation. (CDH1 VCEP specifications version 3.1; 05/06/2022) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at