16-68833364-C-G

Variant names:

• chr16-68833364-C-G
• rs770974998
• NM_004360.5:c.2514C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_004360.5(CDH1):​c.2514C>G​(p.Ser838Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -4.96

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 3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity CADH1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3003704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2514C>G	p.Ser838Arg	missense_variant	Exon 16 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2331C>G	p.Ser777Arg	missense_variant	Exon 15 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.966C>G	p.Ser322Arg	missense_variant	Exon 16 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.549C>G	p.Ser183Arg	missense_variant	Exon 15 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2514C>G	p.Ser838Arg	missense_variant	Exon 16 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Apr 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 838 of the CDH1 protein (p.Ser838Arg). 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: 857052). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S838R variant (also known as c.2514C>G), located in coding exon 16 of the CDH1 gene, results from a C to G substitution at nucleotide position 2514. The serine at codon 838 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.8
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.044	N
LIST_S2	Uncertain	0.87	D;D;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D;.;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.36
MutPred		0.50		Loss of glycosylation at S838 (P = 0.005);.;.;
MVP		0.65
MPC		0.94
ClinPred		0.99	D
GERP RS		-12
Varity_R		0.81
gMVP		0.62

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: rs770974998; hg19: chr16-68867267;