NM_000251.3(MSH2):c.2576_2584del (p.Glu859_Gln861del) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Sep 5, 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:: RCV000128935.20

Allele description [Variation Report for NM_000251.3(MSH2):c.2576_2584del (p.Glu859_Gln861del)]

NM_000251.3(MSH2):c.2576_2584del (p.Glu859_Gln861del)

Gene:

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.2576_2584del (p.Glu859_Gln861del)

HGVS:

NC_000002.11:g.47707950_47707958del
NC_000002.12:g.47480813_47480821del
NG_007110.2:g.82690_82698del
NM_000251.3:c.2576_2584delMANE SELECT
NM_001258281.1:c.2378_2386del
NP_000242.1:p.Glu859_Gln861del
NP_001245210.1:p.Glu793_Gln795del
LRG_218:g.82690_82698del
NC_000002.11:g.47707950_47707958del
NC_000002.11:g.47707952_47707960del
NC_000002.11:g.47707952_47707960delAATCGCAAG
NM_000251.1:c.2576_2584delAATCGCAAG
NM_000251.2:c.2576_2584delAATCGCAAG
NM_000251.3:c.2576_2584delAATCGCAAGMANE SELECT
p.E859_Q861del

Links:

dbSNP: rs587781278

NCBI 1000 Genomes Browser:

rs587781278

Molecular consequence:

NM_000251.3:c.2576_2584del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258281.1:c.2378_2386del - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172806	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Feb 21, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15254659, 18990764, 27443514, 30374176 Citation Link,
SCV000685059	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15713769, 18990764, 27443514, 30374176, 25741868
SCV002534490	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Dec 17, 2021)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 15713769, 18990764, 27443514, 30374176 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000172806

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Feb 21, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000685059

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 5, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002534490

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Dec 17, 2021)

germline

curation

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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, curation

Citations

PubMed

Immunohistochemical detection of the hMLH1 and hMSH2 proteins in hereditary non-polyposis colon cancer and sporadic colon cancer.

Plevová P, Krepelová A, Papezová M, Sedláková E, Curík R, Foretová L, Navrátilová M, Novotný J, Zapletalová J, Palas J, Nieslanik J, Horácek J, Dvorácková J, Kolár Z.

Neoplasma. 2004;51(4):275-84.

PubMed [citation]

PMID:: 15254659

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000172806.9

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

Description

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.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000685059.5

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

Description

This variant causes an in-frame deletion of three amino acids (Glu859-Gln861) in exon 15 of the MSH2 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least one individual each affected with endometrial and early onset colorectal cancer, in the latter case the tumor sample showed the presence of MSH2 by immunohistochemistry (PMID: 15713769, 18990764, 27443514). A multifactorial analysis based on family study data has reported this variant as likely benign due in part to cosegregation likelihood ratio of 0.2554 from one observed family (PMID: 30374176). This variant has been identified in 6/282854 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.

#	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 Sema4, Sema4, SCV002534490.1

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

#	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

Last Updated: Oct 20, 2024

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