rs201511530

chr16-68808832-G-Achr16-68808832-G-Cchr16-68808832-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004360.5(CDH1):c.671G>A(p.Arg224His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R224C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel U:5 B:9
• Conservation: PhyloP100: 0.137

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050248623).
• BP6: Variant 16-68808832-G-A is Benign according to our data. Variant chr16-68808832-G-A is described in ClinVar as [Benign]. Clinvar id is 41786.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.671G>A	p.Arg224His	missense_variant	5/16	ENST00000261769.10
CDH1	NM_001317184.2	c.671G>A	p.Arg224His	missense_variant	5/15
CDH1	NM_001317185.2	c.-945G>A		5_prime_UTR_variant	5/16
CDH1	NM_001317186.2	c.-1149G>A		5_prime_UTR_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.671G>A	p.Arg224His	missense_variant	5/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250850 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135572

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74322

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000194 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:5 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:2 Benign:5

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Feb 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	BP2_Strong; BS2 (PMID: 30311375) -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 18, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 12, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 18, 2020	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. -

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, or prostate cancer (Lu 2015, Hauke 2018, Huang 2018); This variant is associated with the following publications: (PMID: 22703879, 25583476, 26689913, 27720647, 26486520, 26517685, 28135145, 25503501, 29522266, 15235021, 22850631, 29625052) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Feb 23, 2017

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 09, 2023

The c.671G>A (p.Arg224His) missense variant has a frequency of 0. 0.00003189 (8 of 250,850) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00006179 (7 of 113,278) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >50 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; SCV000637843.5, SCV000278911.9). This variant was observed in the homozygous state in an individual without DGC, SRC tumors or LBC and whose family does not suggest HDGC (BP2_Strong, internal laboratory contributor). In summary, the clinical significance of this variant is classified as benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	2.2
Dann	Benign	0.59
DEOGEN2	Benign	0.18	T;T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.62	T;T;T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.050	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.35	N;.;.;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.36	N;.;.;.;N
REVEL	Benign	0.070
Sift	Benign	0.31	T;.;.;.;T
Sift4G	Benign	0.48	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.078
MVP		0.72
MPC		0.31
ClinPred		0.020	T
GERP RS		-2.9
Varity_R		0.14
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs201511530; hg19: chr16-68842735; COSMIC: COSV55729764; COSMIC: COSV55729764;