rs876658680

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM2_SupportingBS2

This summary comes from the ClinGen Evidence Repository: The c.161G>A (p.Arg54Lys) missense variant is absent in the gnomAD 2.1.1 cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been observed in ≥10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000274257.4, SCV000637737.4, unpublished data). In summary, although a conflicting code PM2_supporting is met, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2_supporting, BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10580076/MONDO:0100488/007

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense, splice_region

Scores

Splicing: ADA: 0.0003592

Clinical Significance

Likely benign reviewed by expert panel U:4B:1

Conservation

PhyloP100: 0.361

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]

CDH1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5 link	c.161G>A	p.Arg54Lys	missense_variant, splice_region_variant	Exon 2 of 16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDH1	ENST00000261769.10 link	c.161G>A	p.Arg54Lys	missense_variant, splice_region_variant	Exon 2 of 16	1	NM_004360.5	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6 link	c.161G>A	p.Arg54Lys	missense_variant, splice_region_variant	Exon 2 of 15	1		ENSP00000414946.2	P12830-2
CDH1	ENST00000566612.5 link	n.161G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000454782.1	H3BNC6
CDH1	ENST00000566510.5 link	n.161G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 15	5		ENSP00000458139.1	H3BVI7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000288

AC:

AN:

1391146

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

685650

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:

0.00

Gnomad4 NFE exome

AF:

0.00000373

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Apr 16, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R54K variant (also known as c.161G>A), located in coding exon 2 of the CDH1 gene, results from a G to A substitution at nucleotide position 161. The arginine at codon 54 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Feb 14, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with lysine at codon 54 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 hereditary cancer in the literature. This variant has not been identified 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. -

Hereditary diffuse gastric adenocarcinoma

Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 54 of the CDH1 protein (p.Arg54Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 230641). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Aug 02, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.161G>A (p.Arg54Lys) missense variant is absent in the gnomAD 2.1.1 cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been observed in at least 10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000274257.4, SCV000637737.4, unpublished data). In summary, although a conflicting code PM2_supporting is met, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2_supporting, BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.16

T;T;T;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.53

T;T;T;T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;.;.;L

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.16

N;.;.;.;N

REVEL

Benign

0.048

Sift

Benign

1.0

T;.;.;.;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.015

B;.;.;.;.

Vest4

0.31

MutPred

0.64

Gain of ubiquitination at R54 (P = 0.0325);Gain of ubiquitination at R54 (P = 0.0325);Gain of ubiquitination at R54 (P = 0.0325);Gain of ubiquitination at R54 (P = 0.0325);Gain of ubiquitination at R54 (P = 0.0325);

MVP

0.76

MPC

0.26

ClinPred

0.23

GERP RS

2.7

Varity_R

0.11

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00036

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over