rs863224726

chr16-68819327-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP5_Strong

The NM_004360.5(CDH1):c.1613A>T(p.Asp538Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D538N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 4.32

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68819327-A-T is Pathogenic according to our data. Variant chr16-68819327-A-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 216589.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1613A>T	p.Asp538Val	missense_variant	11/16	ENST00000261769.10
CDH1	NM_001317184.2	c.1430A>T	p.Asp477Val	missense_variant	10/15
CDH1	NM_001317185.2	c.65A>T	p.Asp22Val	missense_variant	11/16
CDH1	NM_001317186.2	c.-254-2674A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1613A>T	p.Asp538Val	missense_variant	11/16	1	NM_004360.5	P1
	ENST00000563916.1	n.264-3668T>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 216589). This missense change has been observed in individuals with clinical features of hereditary diffuse gastric and lobular breast cancer syndrome (Invitae; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 538 of the CDH1 protein (p.Asp538Val). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.1613A>T variant (also known as p.D538V), located in coding exon 11 of the CDH1 gene, results from an A to T substitution at nucleotide position 1613. The aspartic acid at codon 538 is replaced by valine, an amino acid with highly dissimilar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with CDH1-related disease (Ambry internal data, personal communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Uncertain significance, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 21, 2023

The c.1613A>T (p.Asp538Val) variant is absent in the gnomAD cohort (PM2_Supporting). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; SCV000254814.3). In summary, this variant meets criteria to be classified as a variant of uncertain significance based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS4_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T;T;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.62	T;T;T;T;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.0	L;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-4.2	D;.;.;.;D
REVEL	Benign	0.26
Sift	Benign	0.46	T;.;.;.;T
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		0.92	P;.;.;.;.
Vest4		0.39
MutPred		0.43		Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);.;Loss of solvent accessibility (P = 0.0561);.;
MVP		0.87
MPC		0.80
ClinPred		0.97	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863224726; hg19: chr16-68853230;