NM_000251.3(MSH2):c.499G>C (p.Asp167His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Aug 11, 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:: RCV001284654.8

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Metagenome-Assembled Genome: SRR18940287_bin.18_MetaWRAP_v1.3_MAG
Metagenome-Assembled Genome: SRR18940287_bin.18_MetaWRAP_v1.3_MAG

biosample
Bacillus pumilus strain B-254 16S ribosomal RNA gene, partial sequence
Bacillus pumilus strain B-254 16S ribosomal RNA gene, partial sequence
gi|951642760|gb|KT692732.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149442	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Jan 22, 2021)	germline	clinical testing	Citation Link,
SCV001470554	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 11, 2023)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 27601186, 25980754, 22949387, 22102614, 20672385, 18822302, 18781619, 18383312, 17720936, 17192056, 12124176, 11870161, 8872463, 32994724, 33357406, 32941469, 31237724, 31159747, 25637381, 26467025
SCV001554252	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

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000149442

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Jan 22, 2021)

germline

clinical testing

Citation Link,

SCV001470554

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Aug 11, 2023)

unknown

clinical testing

PubMed (20)
[See all records that cite these PMIDs]

SCV001554252

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

See additional submitters

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	unknown	yes	1	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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M.

Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.

PubMed [citation]

PMID:: 27601186

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 (20)

Details of each submission

From GeneDx, SCV000149442.13

#	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 associated with the following publications: (PMID: 17720936, 12124176, 8872463, 26951660, 28125613, 25637381, 18781619, 20672385, 17192056, 15340264, 11870161, 18822302, 22102614, 22949387, 20176959, 11606497, 25980754, 18383312, 17250665, 17594722, 23741719, 19464205, 26333163, 22045683, 27601186, 31159747, 31237724, 31569399)

#	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, SCV001470554.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

In the published literature, this variant has been reported in individuals/families with Lynch syndrome or Lynch syndrome associated cancers (PMID: 32941469 (2020), 27601186 (2016), 11870161 (2002), 8872463 (1996)) or breast cancer (PMID: 32994724 (2020)). Experimental studies have demonstrated this variant has a neutral effect on MSH2 protein function (PMID: 22949387 (2013), 22102614 (2012), 20672385 (2010), 18822302 (2008), 18781619 (2008), 17720936 (2007)). The frequency of this variant in the general population, 0.0002 (6/30616 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001554252.1

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

Last Updated: Jun 2, 2024

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