rs786202290

chr16-68819425-G-Achr16-68819425-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_004360.5(CDH1):c.1711G>A(p.Gly571Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G571D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.84

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_004360.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 16-68819425-G-A is Pathogenic according to our data. Variant chr16-68819425-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185583.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1711G>A	p.Gly571Ser	missense_variant, splice_region_variant	11/16	ENST00000261769.10
CDH1	NM_001317184.2	c.1528G>A	p.Gly510Ser	missense_variant, splice_region_variant	10/15
CDH1	NM_001317185.2	c.163G>A	p.Gly55Ser	missense_variant, splice_region_variant	11/16
CDH1	NM_001317186.2	c.-254-2576G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1711G>A	p.Gly571Ser	missense_variant, splice_region_variant	11/16	1	NM_004360.5	P1
	ENST00000563916.1	n.264-3766C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast;C1708349:Hereditary diffuse gastric adenocarcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.1711G>A variant (also known as p.G571S), located in coding exon 11 of the CDH1 gene, results from a G to A substitution at nucleotide position 1711. The amino acid change results in glycine to serine at codon 571, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This alteration has been detected in a family with a clinical history consistent with hereditary diffuse gastric cancer (Ambry internal data). RNA analysis has shown to cause aberrant splicing in patient-derived lymphoblast cells (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec;:). This nucleotide position is completely conserved on sequence alignment. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive and direct evidence is insufficient at this time (Ambry internal data). In silico splice site analysis for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;T;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Uncertain	0.079	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.6	D;.;.;.;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;.;.;.;D
Sift4G	Benign	0.065	T;D;T;D;T
Polyphen		0.99	D;.;.;.;.
Vest4		0.62
MutPred		0.62		Gain of glycosylation at G571 (P = 0.0497);Gain of glycosylation at G571 (P = 0.0497);.;Gain of glycosylation at G571 (P = 0.0497);.;
MVP		0.93
MPC		0.55
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786202290; hg19: chr16-68853328; COSMIC: COSV55745630; COSMIC: COSV55745630;