NM_000251.3(MSH2):c.499G>C (p.Asp167His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 2, 2022
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:: RCV000115533.19

Allele description [Variation Report for NM_000251.3(MSH2):c.499G>C (p.Asp167His)]

NM_000251.3(MSH2):c.499G>C (p.Asp167His)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.499G>C (p.Asp167His)

Other names:

p.D167H:GAT>CAT

HGVS:

NC_000002.12:g.47410226G>C
NG_007110.2:g.12103G>C
NM_000251.3:c.499G>CMANE SELECT
NM_001258281.1:c.301G>C
NP_000242.1:p.Asp167His
NP_000242.1:p.Asp167His
NP_001245210.1:p.Asp101His
LRG_218t1:c.499G>C
LRG_218:g.12103G>C
LRG_218p1:p.Asp167His
NC_000002.11:g.47637365G>C
NM_000251.1:c.499G>C
NM_000251.2:c.499G>C
P43246:p.Asp167His
p.D167H

Protein change:

D101H

Links:

UniProtKB: P43246#VAR_004474; dbSNP: rs63750255

NCBI 1000 Genomes Browser:

rs63750255

Molecular consequence:

NM_000251.3:c.499G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.301G>C - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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Homo sapiens PNAS-125 mRNA, complete cds
Homo sapiens PNAS-125 mRNA, complete cds
gi|12751095|gb|AF277183.1|

Nucleotide
Homo sapiens PKCq-interacting protein PICOT (PICOT) mRNA, complete cds
Homo sapiens PKCq-interacting protein PICOT (PICOT) mRNA, complete cds
gi|6840952|gb|AF118652.1|

Nucleotide
Olmsted syndrome 1
Olmsted syndrome 1

MedGen

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000212799	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Apr 16, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17720936, 18383312, 18781619, 18822302, 20672385, 22102614 Citation Link,
SCV000690113	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jan 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000822054	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002534526	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Benign (Jan 26, 2021)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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, curation

Citations

PubMed

Functional characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae.

Gammie AE, Erdeniz N, Beaver J, Devlin B, Nanji A, Rose MD.

Genetics. 2007 Oct;177(2):707-21. Epub 2007 Aug 24.

PubMed [citation]

PMID:: 17720936
PMCID:: PMC2034637

Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR).

Chao EC, Velasquez JL, Witherspoon MS, Rozek LS, Peel D, Ng P, Gruber SB, Watson P, Rennert G, Anton-Culver H, Lynch H, Lipkin SM.

Hum Mutat. 2008 Jun;29(6):852-60. doi: 10.1002/humu.20735.

PubMed [citation]

PMID:: 18383312

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000212799.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

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, SCV000690113.3

#	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 GeneKor MSA, SCV000822054.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002534526.1

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

Last Updated: Oct 8, 2024

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