rs786201287

Positions:

• chr16-68737430-C-A
• chr16-68737430-C-G
• chr16-68737430-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004360.5(CDH1):​c.15C>A​(p.Ser5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,382,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.932

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14307186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.15C>A	p.Ser5Arg	missense_variant	1/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.15C>A	p.Ser5Arg	missense_variant	1/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1601C>A		5_prime_UTR_variant	1/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1805C>A		5_prime_UTR_variant	1/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.15C>A	p.Ser5Arg	missense_variant	1/16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.15C>A	p.Ser5Arg	missense_variant	1/15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.15C>A		non_coding_transcript_exon_variant	1/15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.15C>A		non_coding_transcript_exon_variant	1/15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1382430 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 682538

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Mar 28, 2024

The p.S5R variant (also known as c.15C>A), located in coding exon 1 of the CDH1 gene, results from a C to A substitution at nucleotide position 15. The serine at codon 5 is replaced by arginine, an amino acid with dissimilar properties. 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 available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T;T;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.62	T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.;.;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.64	N;.;.;.;N
REVEL	Benign	0.14
Sift	Benign	0.35	T;.;.;.;T
Sift4G	Benign	0.40	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.27
MutPred		0.44		Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);
MVP		0.78
MPC		0.48
ClinPred		0.11	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.12
gMVP		0.44

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: rs786201287; hg19: chr16-68771333; COSMIC: COSV55732240;