16-68801727-G-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.221G>A (p.Arg74Gln) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA396457187/MONDO:0100488/007
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.221G>A | p.Arg74Gln | missense_variant | Exon 3 of 16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.221G>A | p.Arg74Gln | missense_variant | Exon 3 of 15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.-1395G>A | 5_prime_UTR_variant | Exon 3 of 16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-1599G>A | 5_prime_UTR_variant | Exon 3 of 15 | NP_001304115.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74322
ClinVar
Submissions by phenotype
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:2
The NM_004360.5(CDH1):c.221G>A (p.Arg74Gln) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023). -
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Hereditary cancer-predisposing syndrome Benign:2
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. -
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not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual with familial, non-syndromic cleft lip and/or palate with no information about cancer history (Pengelly 2016); This variant is associated with the following publications: (PMID: 25344691, 28229982, 32175104, 27456059) -
not specified Benign:1
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Hereditary diffuse gastric adenocarcinoma Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at