NM_000251.3(MSH2):c.138C>G (p.His46Gln) AND Lynch syndrome 1

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Feb 27, 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:: RCV000986643.15

Allele description [Variation Report for NM_000251.3(MSH2):c.138C>G (p.His46Gln)]

NM_000251.3(MSH2):c.138C>G (p.His46Gln)

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.138C>G (p.His46Gln)

Other names:

p.H46Q:CAC>CAG

HGVS:

NC_000002.12:g.47403329C>G
NG_007110.2:g.5206C>G
NM_000251.3:c.138C>GMANE SELECT
NM_001258281.1:c.-30-31C>G
NP_000242.1:p.His46Gln
NP_000242.1:p.His46Gln
LRG_218t1:c.138C>G
LRG_218:g.5206C>G
LRG_218p1:p.His46Gln
NC_000002.11:g.47630468C>G
NM_000251.1:c.138C>G
NM_000251.2:c.138C>G
P43246:p.His46Gln
p.H46Q

Protein change:

H46Q

Links:

UniProtKB: P43246#VAR_004470; dbSNP: rs33946261

NCBI 1000 Genomes Browser:

rs33946261

Molecular consequence:

NM_001258281.1:c.-30-31C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000251.3:c.138C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Lynch syndrome 1
Synonyms:: COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 1; MSH2-Related Hereditary Non-Polyposis Colon Cancer; Lynch syndrome I; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007356; MedGen: C2936783; Orphanet: 144; OMIM: 120435

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001135691	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Likely benign (Feb 27, 2023)	germline	clinical testing	Citation Link,
SCV001302263	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23047549, 18033691, 15520370, 25637381, 19389263, 24728327, 15872200 Citation Link,
SCV002761451	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 22, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28195393, 30374176, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001135691

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2019)

Likely benign
(Feb 27, 2023)

germline

clinical testing

Citation Link,

SCV001302263

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV002761451

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Apr 22, 2020)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

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

Citations

PubMed

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

Pal T, Akbari MR, Sun P, Lee JH, Fulp J, Thompson Z, Coppola D, Nicosia S, Sellers TA, McLaughlin J, Risch HA, Rosen B, Shaw P, Schildkraut J, Narod SA.

Br J Cancer. 2012 Nov 6;107(10):1783-90. doi: 10.1038/bjc.2012.452. Epub 2012 Oct 9.

PubMed [citation]

PMID:: 23047549
PMCID:: PMC3493867

Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer.

Barnetson RA, Cartwright N, van Vliet A, Haq N, Drew K, Farrington S, Williams N, Warner J, Campbell H, Porteous ME, Dunlop MG.

Hum Mutat. 2008 Mar;29(3):367-74.

PubMed [citation]

PMID:: 18033691

See all PubMed Citations (10)

Details of each submission

From Mendelics, SCV001135691.2

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

From Illumina Laboratory Services, Illumina, SCV001302263.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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 Genetics and Molecular Pathology, SA Pathology, SCV002761451.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The MSH2 c.138C>G variant is classified as Likely Benign (BS4, BP6, PP3) The MSH2 c.138C>G variant is a single nucleotide change in exon 1 of 16 of the MSH2 gene, which is predicted to change the amino acid histidine at position 46 in the protein to glutamine. This variant does not segregate with disease (BS4). PMID: 28195393- segregation analysis does not support pathogenicity. Variant identified in 0 out of 3 affected family members and 3 out of 9 unaffected family members. PMID:30374176 - family studies do not support pathogenicity

#	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

Last Updated: Oct 13, 2024

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