VCV000136062.29 - ClinVar

NM_004360.5(CDH1):c.1865A>G (p.Asn622Ser)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Likely benign

for CDH1-related diffuse gastric and lobular breast cancer syndrome

Classification is based on the expert panel submission

Aug 2023 by ClinGen CDH1 Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004360.5(CDH1):c.1865A>G (p.Asn622Ser)

Variation ID: 136062 Accession: VCV000136062.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q22.1 16: 68822154 (GRCh38) [ NCBI UCSC ] 16: 68856057 (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	Jun 16, 2014	Feb 25, 2025	Aug 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004360.5:c.1865A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004351.1:p.Asn622Ser	missense
NM_001317184.2:c.1682A>G	NP_001304113.1:p.Asn561Ser	missense
NM_001317185.2:c.317A>G	NP_001304114.1:p.Asn106Ser	missense
NM_001317186.2:c.-101A>G		5 prime UTR
NC_000016.10:g.68822154A>G
NC_000016.9:g.68856057A>G
NG_008021.1:g.89863A>G
LRG_301:g.89863A>G
LRG_301t1:c.1865A>G

... more HGVS ... less HGVS

Protein change

N622S, N561S, N106S

Other names

NM_004360.5(CDH1):c.1865A>G
p.Asn622Ser

Canonical SPDI

NC_000016.10:68822153: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), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA167846 dbSNP: rs147925149 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	4837	4932

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 diffuse gastric adenocarcinoma	Conflicting classifications of pathogenicity (5)	criteria provided, conflicting classifications	Jul 20, 2024	RCV000123241.20
Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Feb 17, 2023	RCV000131244.11
not provided	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Feb 20, 2024	RCV000286705.10
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 10, 2022	RCV001824619.2
CDH1-related diffuse gastric and lobular breast cancer syndrome	Likely benign (1)	reviewed by expert panel	Aug 17, 2023	RCV003328192.2

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 17, 2023) C Contributing to aggregate classification	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: SCV001943360.2 First in ClinVar: Sep 29, 2021 Last updated: Sep 20, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fb75729d-4b06-40ec-a9b2-4ef0998a31d7 Comment: The c.1865A>G (p.Asn622Ser) missense variant has a frequency of 0.000007953 (2 of 251,480) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of … (more) The c.1865A>G (p.Asn622Ser) missense variant has a frequency of 0.000007953 (2 of 251,480) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00006152 (1 of 16,256) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >10 (27) individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; SCV000166547.6, SCV000329232.7). 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 (Variant Interpretation Guidelines Version 3.1): BS2. (less)
Uncertain significance (May 25, 2016) N Not contributing to aggregate classification	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: SCV000488709.2 First in ClinVar: Jun 16, 2014 Last updated: Dec 24, 2022
Likely benign (Sep 08, 2022) N Not contributing to aggregate classification	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: SCV001134069.3 First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024	Publications: PubMed (1) PubMed: 33471991
Likely benign (Nov 18, 2021) N Not contributing to aggregate classification	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: SCV000186201.8 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)
Uncertain significance (Feb 20, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329232.9 First in ClinVar: Dec 06, 2016 Last updated: Sep 16, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15235021, 22850631, 33471991, 36436516) (less)
Uncertain significance (Jan 10, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002074187.1 First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022
Likely benign (Aug 01, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (Lee et al. (Hum Mutat. 2018)) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma (Autosomal dominant inheritance) Affected status: no Allele origin: germline	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto Study: ERN GENTURIS Accession: SCV003926863.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (1) PubMed: 36436516 Comment: BS2 (PMID: 30311375) Geographic origin: Europe Comment on evidence: 1 family not fulfilling 2020 HDGC criteria-Familial history of breast cancer
Uncertain significance (Feb 17, 2023) N Not contributing to aggregate classification	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: SCV001348201.2 First in ClinVar: Mar 25, 2020 Last updated: Feb 14, 2024	Comment: This missense variant replaces asparagine with serine at codon 622 of the CDH1 protein. To our knowledge, functional studies have not been reported for this … (more) This missense variant replaces asparagine with serine at codon 622 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 CDH1-related disorders in the literature. This variant has been identified in 2/251480 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. (less)
Uncertain significance (Sep 09, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV000890923.2 First in ClinVar: Mar 19, 2019 Last updated: Aug 11, 2021
Uncertain significance (Mar 06, 2023) N Not contributing to aggregate classification	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: SCV004020021.1 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.
Likely benign (Jul 20, 2024) N Not contributing to aggregate classification	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: SCV000166547.10 First in ClinVar: Jun 16, 2014 Last updated: Feb 25, 2025	Publications: PubMed (1) PubMed: 28492532
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Comment:

The c.1865A>G (p.Asn622Ser) missense variant has a frequency of 0.000007953 (2 of 251,480) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00006152 (1 of 16,256) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >10 (27) individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; SCV000166547.6, SCV000329232.7). 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 (Variant Interpretation Guidelines Version 3.1): BS2.

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.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15235021, 22850631, 33471991, 36436516)

Comment:

This missense variant replaces asparagine with serine at codon 622 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 CDH1-related disorders in the literature. This variant has been identified in 2/251480 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.

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
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.	Garcia-Pelaez J	The Lancet. Oncology	2023	PMID: 36436516
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fb75729d-4b06-40ec-a9b2-4ef0998a31d7	-	-	-	-

Text-mined citations for rs147925149 ...

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 Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_004360.5(CDH1):c.1865A>G (p.Asn622Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs147925149 ...