NM_004360.5(CDH1):c.214G>A (p.Asp72Asn) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 9, 2023
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:: RCV000656818.13

Allele description [Variation Report for NM_004360.5(CDH1):c.214G>A (p.Asp72Asn)]

NM_004360.5(CDH1):c.214G>A (p.Asp72Asn)

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.214G>A (p.Asp72Asn)

Other names:

p.D72N:GAC>AAC; NM_004360.5(CDH1):c.214G>A

HGVS:

NC_000016.10:g.68801720G>A
NG_008021.1:g.69429G>A
NM_001317184.2:c.214G>A
NM_001317185.2:c.-1402G>A
NM_001317186.2:c.-1606G>A
NM_004360.5:c.214G>AMANE SELECT
NP_001304113.1:p.Asp72Asn
NP_004351.1:p.Asp72Asn
LRG_301t1:c.214G>A
LRG_301:g.69429G>A
NC_000016.9:g.68835623G>A
NM_004360.3:c.214G>A
NM_004360.4:c.214G>A
P12830:p.Asp72Asn
p.D72N

Protein change:

D72N

Links:

UniProtKB: P12830#VAR_048500; dbSNP: rs35606263

NCBI 1000 Genomes Browser:

rs35606263

Molecular consequence:

NM_001317185.2:c.-1402G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1606G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.214G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.214G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000210893	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Feb 25, 2021)	germline	clinical testing	Citation Link,
SCV000600973	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely benign (Jan 9, 2023)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 30287823, 31784482, 31159747, 33471991, 26467025
SCV000806654	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 12, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001550075	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	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

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]

PMID:: 30287823
PMCID:: PMC6172276

Retesting of women who are negative for a BRCA1 and BRCA2 mutation using a 20-gene panel.

Lerner-Ellis J, Sopik V, Wong A, Lázaro C, Narod SA, Charames GS.

J Med Genet. 2020 Jun;57(6):380-384. doi: 10.1136/jmedgenet-2019-106403. Epub 2019 Nov 29.

PubMed [citation]

PMID:: 31784482

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000210893.13

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

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with lung cancer and in 1/11,241 controls but not in the associated breast cancer cases (Momozawa 2018, Santeufemia 2019); This variant is associated with the following publications: (PMID: 30287823, 30979070, 31159747, 31784482)

#	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	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000600973.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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 PreventionGenetics, part of Exact Sciences, SCV000806654.1

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001550075.1

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

Description

The CDH1 p.Asp72Asn variant was not identified in 14102 proband chromosomes from individuals or families with breast cancer but was present in 4 of 22482 control chromosomes (frequency: 0.0009) from healthy individuals (Momozawa 2018). The variant was also identified in dbSNP (ID: rs35606263) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and five other submitters), and LOVD 3.0 (2x as VUS). The variant was identified in control databases in 29 of 277070 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24020 chromosomes (freq: 0.0001), Latino in 17 of 34418 chromosomes (freq: 0.0005), European in 6 of 126588 chromosomes (freq: 0.00005), Ashkenazi Jewish in 3 of 10148 chromosomes (freq: 0.0003); it was not observed in the Other, East Asian, Finnish, or South Asian populations. The p.Asp72 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

Last Updated: Oct 20, 2024

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