chr16-68819285-G-C

Position:

• chr16-68819285-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004360.5(CDH1):​c.1571G>C​(p.Arg524Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1571G>C	p.Arg524Pro	missense_variant	11/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1388G>C	p.Arg463Pro	missense_variant	10/15		NP_001304113.1
CDH1	NM_001317185.2	c.23G>C	p.Arg8Pro	missense_variant	11/16		NP_001304114.1
CDH1	NM_001317186.2	c.-254-2716G>C		intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1571G>C	p.Arg524Pro	missense_variant	11/16	1	NM_004360.5	ENSP00000261769	P1
	ENST00000563916.1	n.264-3626C>G		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: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The p.R524P variant (also known as c.1571G>C), located in coding exon 11 of the CDH1 gene, results from a G to C substitution at nucleotide position 1571. The arginine at codon 524 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;T;T;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.3	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D;.;.;.;D
REVEL	Uncertain	0.38
Sift	Benign	0.10	T;.;.;.;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.99	D;.;.;.;.
Vest4		0.85
MutPred		0.57		Loss of MoRF binding (P = 0.0031);Loss of MoRF binding (P = 0.0031);.;Loss of MoRF binding (P = 0.0031);.;
MVP		0.88
MPC		1.1
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.55
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-68853188;