16-68822189-G-T

Position:

• chr16-68822189-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_004360.5(CDH1):​c.1900G>T​(p.Ala634Ser) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A634V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.13

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-68822190-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.090973556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1900G>T	p.Ala634Ser	missense_variant	12/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1717G>T	p.Ala573Ser	missense_variant	11/15		NP_001304113.1
CDH1	NM_001317185.2	c.352G>T	p.Ala118Ser	missense_variant	12/16		NP_001304114.1
CDH1	NM_001317186.2	c.-66G>T		5_prime_UTR_variant	11/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1900G>T	p.Ala634Ser	missense_variant	12/16	1	NM_004360.5	ENSP00000261769	P1
	ENST00000563916.1	n.263+1075C>A		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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2023

This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.Ala634 amino acid residue in CDH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12096341, 12588804, 14500541, 15288293, 15735979, 22850631, 29454568). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 843248). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 634 of the CDH1 protein (p.Ala634Ser). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 13, 2023

This missense variant replaces alanine with serine at codon 634 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at this codon, c.1901C>T (p.Ala634Val), is considered disease-causing in ClinVar with reported impact on the variant protein and mRNA splicing (ClinVar variation ID: 12244). However, this variant c.1900G>T (p.Ala634Ser) is not predicted to affect protein function or mRNA splicing. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.15	T;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.052
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	0.92	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.67	N;.;N
REVEL	Benign	0.044
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.086
MutPred		0.27		Gain of disorder (P = 0.0441);.;.;
MVP		0.77
MPC		0.23
ClinPred		0.32	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060501240; hg19: chr16-68856092;