rs587781701

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The ENST00000261769.10(CDH1):​c.2017C>A​(p.Gln673Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. Q673H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

CDH1
ENST00000261769.10 missense

Scores

1
3
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2

Conservation

PhyloP100: 2.93
Variant links:
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.28850138).
BP6
Variant 16-68823479-C-A is Benign according to our data. Variant chr16-68823479-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141376.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.
BS2
High AC in GnomAdExome4 at 101 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH1NM_004360.5 linkuse as main transcriptc.2017C>A p.Gln673Lys missense_variant 13/16 ENST00000261769.10 NP_004351.1
CDH1NM_001317184.2 linkuse as main transcriptc.1834C>A p.Gln612Lys missense_variant 12/15 NP_001304113.1
CDH1NM_001317185.2 linkuse as main transcriptc.469C>A p.Gln157Lys missense_variant 13/16 NP_001304114.1
CDH1NM_001317186.2 linkuse as main transcriptc.52C>A p.Gln18Lys missense_variant 12/15 NP_001304115.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.2017C>A p.Gln673Lys missense_variant 13/161 NM_004360.5 ENSP00000261769 P1P12830-1
ENST00000563916.1 linkuse as main transcriptn.48G>T non_coding_transcript_exon_variant 1/34

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152032
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251476
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000527
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000691
AC:
101
AN:
1461848
Hom.:
0
Cov.:
33
AF XY:
0.0000784
AC XY:
57
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000863
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152032
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74254
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 03, 2023In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal or family history of breast cancer (Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 15235021, 22850631, 36436516) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoFeb 24, 2020- -
Hereditary diffuse gastric adenocarcinoma Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingEuropean Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of PortoAug 01, 2022Not applicable criteria (PMID: 30311375) -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 07, 2022This missense variant replaces glutamine with lysine at codon 673 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 7/251476 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. -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 15, 2021This 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 23, 2024Variant summary: CDH1 c.2017C>A (p.Gln673Lys) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2017C>A in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. c.2017C>A was detected in 2/9884 individuals in the FLOSSIES database (women older than age 70 without cancer). ClinVar contains an entry for this variant (Variation ID: 141376). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJul 20, 2021- -
CDH1-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 16, 2024The CDH1 c.2017C>A variant is predicted to result in the amino acid substitution p.Gln673Lys. This variant has been reported in the literature in an individual with a family history of breast cancer (Garcia-Pelaez J et al. 2022. PubMed ID: 36436516). This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141376/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 25, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
0.0076
T
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
26
DANN
Benign
0.84
DEOGEN2
Benign
0.31
T;T;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.69
T;T;T
M_CAP
Benign
0.042
D
MetaRNN
Benign
0.29
T;T;T
MetaSVM
Benign
-0.52
T
MutationAssessor
Uncertain
2.8
M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-1.9
N;.;N
REVEL
Benign
0.24
Sift
Benign
0.095
T;.;D
Sift4G
Benign
0.15
T;T;T
Polyphen
0.94
P;.;.
Vest4
0.48
MutPred
0.48
Gain of methylation at Q673 (P = 0.0262);.;.;
MVP
0.83
MPC
0.80
ClinPred
0.38
T
GERP RS
6.0
Varity_R
0.31
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587781701; hg19: chr16-68857382; COSMIC: COSV104558684; COSMIC: COSV104558684; API