NM_004360.5(CDH1):c.826C>G (p.Leu276Val) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 10, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000459067.12

Allele description [Variation Report for NM_004360.5(CDH1):c.826C>G (p.Leu276Val)]

NM_004360.5(CDH1):c.826C>G (p.Leu276Val)

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.826C>G (p.Leu276Val)

HGVS:

NC_000016.10:g.68810335C>G
NG_008021.1:g.78044C>G
NM_001317184.2:c.826C>G
NM_001317185.2:c.-790C>G
NM_001317186.2:c.-994C>G
NM_004360.5:c.826C>GMANE SELECT
NP_001304113.1:p.Leu276Val
NP_004351.1:p.Leu276Val
LRG_301t1:c.826C>G
LRG_301:g.78044C>G
NC_000016.9:g.68844238C>G
NM_004360.3:c.826C>G

Protein change:

L276V

Links:

dbSNP: rs750911401

NCBI 1000 Genomes Browser:

rs750911401

Molecular consequence:

NM_001317185.2:c.-790C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-994C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.826C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.826C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000545431	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000785539	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Sep 6, 2017)	unknown	clinical testing	Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV004019543	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Mar 3, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000545431

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 10, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000785539

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Sep 6, 2017)

unknown

clinical testing

Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf,

Citation Link,

SCV004019543

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Uncertain significance
(Mar 3, 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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	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

Details of each submission

From Invitae, SCV000545431.9

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 276 of the CDH1 protein (p.Leu276Val). This variant is present in population databases (rs750911401, gnomAD 0.0009%). 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: 230201). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

#	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, SCV000785539.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004019543.1

#	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: Aug 11, 2024

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