rs1060501247

Positions:

• chr16-68801705-G-A
• chr16-68801705-G-C
• chr16-68801705-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_004360.5(CDH1):​c.199G>A​(p.Ala67Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,848 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A67D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 1.11

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25465313).
• BS2: High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.199G>A	p.Ala67Thr	missense_variant	3/16	ENST00000261769.10
CDH1	NM_001317184.2	c.199G>A	p.Ala67Thr	missense_variant	3/15
CDH1	NM_001317185.2	c.-1417G>A		5_prime_UTR_variant	3/16
CDH1	NM_001317186.2	c.-1621G>A		5_prime_UTR_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.199G>A	p.Ala67Thr	missense_variant	3/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251456 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 17, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 67 of the CDH1 protein (p.Ala67Thr). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 406667). 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 tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 03, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 26, 2021	This missense variant replaces alanine with threonine at codon 67 of the CDH1 protein. 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 been identified in 3/251456 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 14, 2023	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.79	T;D;T;D;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L;.;.;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.94	N;.;.;.;N
REVEL	Benign	0.12
Sift	Benign	0.39	T;.;.;.;T
Sift4G	Benign	0.41	T;T;T;T;T
Polyphen		0.77	P;.;.;.;.
Vest4		0.17
MutPred		0.54		Gain of glycosylation at A67 (P = 0.0503);Gain of glycosylation at A67 (P = 0.0503);Gain of glycosylation at A67 (P = 0.0503);Gain of glycosylation at A67 (P = 0.0503);Gain of glycosylation at A67 (P = 0.0503);
MVP		0.81
MPC		0.45
ClinPred		0.12	T
GERP RS		5.4
Varity_R		0.14
gMVP		0.25

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: rs1060501247; hg19: chr16-68835608;