NM_000251.3(MSH2):c.164G>A (p.Arg55Gln) AND Lynch syndrome

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Dec 19, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000781988.3

Allele description [Variation Report for NM_000251.3(MSH2):c.164G>A (p.Arg55Gln)]

NM_000251.3(MSH2):c.164G>A (p.Arg55Gln)

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.164G>A (p.Arg55Gln)

HGVS:

NC_000002.12:g.47403355G>A
NG_007110.2:g.5232G>A
NM_000251.3:c.164G>AMANE SELECT
NM_001258281.1:c.-30-5G>A
NP_000242.1:p.Arg55Gln
NP_000242.1:p.Arg55Gln
LRG_218t1:c.164G>A
LRG_218:g.5232G>A
LRG_218p1:p.Arg55Gln
NC_000002.11:g.47630494G>A
NM_000251.1:c.164G>A
NM_000251.2:c.164G>A

Protein change:

R55Q

Links:

dbSNP: rs748196422

NCBI 1000 Genomes Browser:

rs748196422

Molecular consequence:

NM_001258281.1:c.-30-5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000251.3:c.164G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

Recent activity

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interleukin-13 isoform b [Homo sapiens]
interleukin-13 isoform b [Homo sapiens]
gi|1238777609|ref|NP_001341921.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000920444	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v2.4)	Likely benign (Dec 19, 2018)	germline	curation	Citation Link,
SCV004831927	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000920444

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v2.4)

Likely benign
(Dec 19, 2018)

germline

curation

Citation Link,

SCV004831927

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 2, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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	curation
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

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

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000920444.1

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

Description

Multifactorial likelihood analysis posterior probability < 0.05 (0.004)

#	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 All of Us Research Program, National Institutes of Health, SCV004831927.1

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

Description

This missense variant replaces arginine with glutamine at codon 55 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with endometrial cancer with a family history of Lynch syndrome (www.umd.be). Other affected individuals from this family carried a variant in the MSH6 gene. This variant has been identified in 7/233024 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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