rs876660221

chr16-68811772-A-Cchr16-68811772-A-Gchr16-68811772-A-T

Variant summary

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

The NM_004360.5(CDH1):c.921A>C(p.Gln307His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q307Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.160

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.921A>C	p.Gln307His	missense_variant	7/16	ENST00000261769.10
CDH1	NM_001317184.2	c.921A>C	p.Gln307His	missense_variant	7/15
CDH1	NM_001317185.2	c.-695A>C		5_prime_UTR_variant	7/16
CDH1	NM_001317186.2	c.-899A>C		5_prime_UTR_variant	7/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.921A>C	p.Gln307His	missense_variant	7/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 14, 2016

In summary, this variant is a novel missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CDH1-related disease. This sequence change replaces glutamine with histidine at codon 307 of the CDH1 protein (p.Gln307His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;T;T;.;.
Eigen	Benign	0.068
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.5	L;.;.;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.8	D;.;.;.;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;.;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.51
MutPred		0.72		Gain of disorder (P = 0.1443);Gain of disorder (P = 0.1443);Gain of disorder (P = 0.1443);Gain of disorder (P = 0.1443);Gain of disorder (P = 0.1443);
MVP		0.77
MPC		0.88
ClinPred		1.0	D
GERP RS		-0.41
Varity_R		0.94
gMVP		0.75

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: rs876660221; hg19: chr16-68845675;