VCV000141854.21 - ClinVar

NM_004360.5(CDH1):c.1684A>G (p.Thr562Ala)

Germline

Top reviewed classifications are shown here.

Submission summary:

10 submissions

10 submitters

5 conditions

Reviewed by expert panel

Likely benign

Aug 2023 by ClinGen CDH1 V… FDA Recognized Database

for CDH1-related diffuse gastric and lobular breast cancer syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004360.5(CDH1):c.1684A>G (p.Thr562Ala)

Variation ID: 141854 Accession: VCV000141854.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q22.1 16: 68819398 (GRCh38) [ NCBI UCSC ] 16: 68853301 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 1, 2016	May 1, 2024	Aug 3, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004360.5:c.1684A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004351.1:p.Thr562Ala	missense
NM_001317184.2:c.1501A>G	NP_001304113.1:p.Thr501Ala	missense
NM_001317185.2:c.136A>G	NP_001304114.1:p.Thr46Ala	missense
NM_001317186.2:c.-254-2603A>G		intron variant
NC_000016.10:g.68819398A>G
NC_000016.9:g.68853301A>G
NG_008021.1:g.87107A>G
LRG_301:g.87107A>G
LRG_301t1:c.1684A>G

... more HGVS ... less HGVS

Protein change

T562A, T501A, T46A

Other names

NM_004360.5(CDH1):c.1684A>G
p.Thr562Ala

Canonical SPDI

NC_000016.10:68819397:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA166617 dbSNP: rs587782061 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CDH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4456	4550

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary cancer-predisposing syndrome	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jun 28, 2021	RCV000130539.18
Hereditary diffuse gastric adenocarcinoma	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 27, 2024	RCV000233909.22
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jun 26, 2020	RCV001283957.12
CDH1-related diffuse gastric and lobular breast cancer syndrome	Likely benign (1)	reviewed by expert panel	Aug 3, 2023	RCV003328216.4
CDH1-related disorder	Uncertain significance (1)	criteria provided, single submitter	May 30, 2023	RCV003390820.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Aug 03, 2023)	reviewed by expert panel (ClinGen CDH1 ACMG Specifications V3.1) Method: curation	CDH1-related diffuse gastric and lobular breast cancer syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen CDH1 Variant Curation Expert Panel FDA Recognized Database Accession: SCV004035103.1 First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/77378953-408f-4bee-85e0-ebd5248943f7 Comment: The NM_004360.5(CDH1):c.1684A>G (p.Thr562Ala) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and … (more) The NM_004360.5(CDH1):c.1684A>G (p.Thr562Ala) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023) (less)
Uncertain significance (Jun 26, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001469486.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Likely benign (Nov 28, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000517007.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Likely benign (Jun 28, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529084.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Likely benign (May 25, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000689476.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Uncertain significance (Mar 11, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488384.2 First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022
Uncertain significance (Mar 06, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004019593.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: 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.
Uncertain significance (May 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CDH1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119104.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The CDH1 c.1684A>G variant is predicted to result in the amino acid substitution p.Thr562Ala. To our knowledge, this variant has not been reported in the … (more) The CDH1 c.1684A>G variant is predicted to result in the amino acid substitution p.Thr562Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68853301-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Likely benign (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000288444.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532
Likely benign (Mar 25, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000185408.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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. (less)

Comment:

The NM_004360.5(CDH1):c.1684A>G (p.Thr562Ala) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023)

Comment:

The CDH1 c.1684A>G variant is predicted to result in the amino acid substitution p.Thr562Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68853301-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

This alteration is classified as likely 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/77378953-408f-4bee-85e0-ebd5248943f7	-	-	-	-

Text-mined citations for rs587782061 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_004360.5(CDH1):c.1684A>G (p.Thr562Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587782061 ...