NM_004360.5:c.1143G>C
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2
The NM_004360.5(CDH1):c.1143G>C(p.Lys381Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,158 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K381R) has been classified as Uncertain significance.
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: Benign. The variant received -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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CDH1 | NM_004360.5 | c.1143G>C | p.Lys381Asn | missense_variant | Exon 9 of 16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317185.2 | c.-473G>C | 5_prime_UTR_variant | Exon 9 of 16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-677G>C | 5_prime_UTR_variant | Exon 9 of 15 | NP_001304115.1 | |||
CDH1 | NM_001317184.2 | c.1137+1055G>C | intron_variant | Intron 8 of 14 | NP_001304113.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152176Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000358 AC: 9AN: 251444 AF XY: 0.0000294 show subpopulations
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727230 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000105 AC: 16AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74462 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:2Benign:2
This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
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 applicable criteria (PMID: 30311375) -
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not specified Uncertain:2
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Variant summary: CDH1 c.1143G>C (p.Lys381Asn) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251444 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has also been reported among at-least 5 women who are reportedly cancer free and older than age 70 (FLOSSIES database). c.1143G>C has been reported in the literature as a VUS in settings of multigene panel testing of individuals affected with BRCA negative breast cancer (example, Weitzel_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1Benign:1
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Weitzel et al., 2019); This variant is associated with the following publications: (PMID: 31206626, 22850631, 15235021) -
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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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Familial cancer of breast;C0476089:Endometrial carcinoma;C1140680:Ovarian cancer;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at