NM_000251.3(MSH2):c.781A>G (p.Met261Val) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 12, 2016
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002230368.14

Allele description [Variation Report for NM_000251.3(MSH2):c.781A>G (p.Met261Val)]

NM_000251.3(MSH2):c.781A>G (p.Met261Val)

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.781A>G (p.Met261Val)

HGVS:

NC_000002.12:g.47412549A>G
NG_007110.2:g.14426A>G
NM_000251.3:c.781A>GMANE SELECT
NM_001258281.1:c.583A>G
NP_000242.1:p.Met261Val
NP_000242.1:p.Met261Val
NP_001245210.1:p.Met195Val
LRG_218t1:c.781A>G
LRG_218:g.14426A>G
LRG_218p1:p.Met261Val
NC_000002.11:g.47639688A>G
NM_000251.1:c.781A>G
NM_000251.2:c.781A>G

Protein change:

M195V

Links:

dbSNP: rs786201941

NCBI 1000 Genomes Browser:

rs786201941

Molecular consequence:

NM_000251.3:c.781A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.583A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000548296	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 12, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26530882, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000548296

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 12, 2016)

germline

clinical testing

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Targeted DNA Sequencing Detects Mutations Related to Susceptibility among Familial Non-medullary Thyroid Cancer.

Yu Y, Dong L, Li D, Chuai S, Wu Z, Zheng X, Cheng Y, Han L, Yu J, Gao M.

Sci Rep. 2015 Nov 4;5:16129. doi: 10.1038/srep16129.

PubMed [citation]

PMID:: 26530882
PMCID:: PMC4632085

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000548296.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant has been reported in an individual affected with non-medullary thyroid cancer (FNMTC) (PMID: 26530882). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 261 of the MSH2 protein (p.Met261Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine.

#	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: Nov 3, 2024

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