16-68811800-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_004360.5(CDH1):c.949T>C(p.Phe317Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.949T>C | p.Phe317Leu | missense_variant | Exon 7 of 16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.949T>C | p.Phe317Leu | missense_variant | Exon 7 of 15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.-667T>C | 5_prime_UTR_variant | Exon 7 of 16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-871T>C | 5_prime_UTR_variant | Exon 7 of 15 | NP_001304115.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:2
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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 584915). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 317 of the CDH1 protein (p.Phe317Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.F317L variant (also known as c.949T>C), located in coding exon 7 of the CDH1 gene, results from a T to C substitution at nucleotide position 949. The phenylalanine at codon 317 is replaced by leucine, an amino acid with highly similar properties. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at