NM_004360.5(CDH1):c.2512A>G (p.Ser838Gly) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Jan 24, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000198450.31

Allele description [Variation Report for NM_004360.5(CDH1):c.2512A>G (p.Ser838Gly)]

NM_004360.5(CDH1):c.2512A>G (p.Ser838Gly)

Gene:

CDH1:cadherin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

NM_004360.5(CDH1):c.2512A>G (p.Ser838Gly)

Other names:

p.S838G:AGC>GGC

HGVS:

NC_000016.10:g.68833362A>G
NG_008021.1:g.101071A>G
NM_001317184.2:c.2329A>G
NM_001317185.2:c.964A>G
NM_001317186.2:c.547A>G
NM_004360.5:c.2512A>GMANE SELECT
NP_001304113.1:p.Ser777Gly
NP_001304114.1:p.Ser322Gly
NP_001304115.1:p.Ser183Gly
NP_004351.1:p.Ser838Gly
LRG_301t1:c.2512A>G
LRG_301:g.101071A>G
NC_000016.9:g.68867265A>G
NM_004360.3:c.2512A>G
NM_004360.4:c.2512A>G
P12830:p.Ser838Gly
p.S838G
NM_004360.4(CDH1):c.2512A>G

Protein change:

S183G; SER838GLY

Links:

UniProtKB: P12830#VAR_001322; OMIM: 192090.0003; dbSNP: rs121964872

NCBI 1000 Genomes Browser:

rs121964872

Molecular consequence:

NM_001317184.2:c.2329A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.964A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001317186.2:c.547A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.2512A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary diffuse gastric adenocarcinoma (HDGC)
Synonyms:: Hereditary diffuse gastric cancer
Identifiers:: MONDO: MONDO:0007648; MedGen: C1708349; Orphanet: 26106; OMIM: 137215

Recent activity

Clear Turn Off Turn On

Chromosome neighbors for GEO Profiles (Select 44336291) (20)
GEO Profiles
Taxonomy Links for Protein (Select 2124011325) (1)
Taxonomy
Taxonomy Links for Protein (Select 912861922) (1)
Taxonomy
Taxonomy Links for Nucleotide (Select 328461557) (1)
Taxonomy
Nucleotide Links for Protein (Select 2124011385) (2)
Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000254825	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 24, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000487808	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Nov 17, 2015)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22470475, 19139070, 25980754, 8075649 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000788250	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Tsai GJ et al. (Genet Med 2018))	Likely benign (May 26, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001140155	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Benign (Aug 22, 2023)	germline	clinical testing	Citation Link,
SCV001274534	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19139070, 8075649, 22470475 Citation Link,
SCV003926957	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS	criteria provided, single submitter (Lee et al. (Hum Mutat. 2018))	Likely benign (Aug 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30311375, 36436516
SCV004020042	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Mar 7, 2023)	unknown	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	1	not provided	not provided	yes	research
not provided	germline	no	not provided	3	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S.

Gastroenterology. 2015 Sep;149(3):604-13.e20. doi: 10.1053/j.gastro.2015.05.006. Epub 2015 May 14.

PubMed [citation]

PMID:: 25980754
PMCID:: PMC4550537

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000254825.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000487808.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000788250.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	yes	research	PubMed (1)

Description

The CDH1 variant designated as NM_004360.3:c.2512A>G (p.Ser838Gly) is classified as likely benign in the context of hereditary diffuse gastric cancer syndrome (Hansford 2015, PMID:26182300). This variant was identified or imputed in several family members age 65 or older who have not had gastric cancer or lobular breast cancer. This variant is listed in population databases (rs121964872) and is found in approximately 1 out of 9000 individuals of European ancestry (http://gnomad.broadinstitute.org/). This variant is predicted to be tolerated by in silico prediction tools (SIFT, PolyPhen-2, Align-GVGD). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to cause hereditary diffuse gastric cancer syndrome. A smaller increase in cancer risk that the risk reported in the literature due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	1	not provided

From Mendelics, SCV001140155.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001274534.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS, SCV003926957.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

"3 families not fulfilling 2020 HDGC criteria-1 Familial history of breast cancer; 2 Familial history of other cancers than gastric cancer or breast cancer"

PubMed [ID: 36436516]

Description

BS2 (PMID: 30311375)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	3	not provided

From Myriad Genetics, Inc., SCV004020042.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

Relating variation to medicine