NM_000251.3(MSH2):c.127T>C (p.Tyr43His) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 5, 2023
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:: RCV001239570.8

Allele description [Variation Report for NM_000251.3(MSH2):c.127T>C (p.Tyr43His)]

NM_000251.3(MSH2):c.127T>C (p.Tyr43His)

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.127T>C (p.Tyr43His)

HGVS:

NC_000002.12:g.47403318T>C
NG_007110.2:g.5195T>C
NM_000251.3:c.127T>CMANE SELECT
NM_001258281.1:c.-30-42T>C
NP_000242.1:p.Tyr43His
NP_000242.1:p.Tyr43His
LRG_218t1:c.127T>C
LRG_218:g.5195T>C
LRG_218p1:p.Tyr43His
NC_000002.11:g.47630457T>C
NM_000251.1:c.127T>C
NM_000251.2:c.127T>C
p.Y43H

Protein change:

Y43H

Links:

dbSNP: rs786202731

NCBI 1000 Genomes Browser:

rs786202731

Molecular consequence:

NM_001258281.1:c.-30-42T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000251.3:c.127T>C - 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
SCV001412453	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 5, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10612827, 33357406, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001412453

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 5, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

UMD (Universal mutation database): a generic software to build and analyze locus-specific databases.

Béroud C, Collod-Béroud G, Boileau C, Soussi T, Junien C.

Hum Mutat. 2000;15(1):86-94.

PubMed [citation]

PMID:: 10612827

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.

Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M, Kitzman JO.

Am J Hum Genet. 2021 Jan 7;108(1):163-175. doi: 10.1016/j.ajhg.2020.12.003. Epub 2020 Dec 23.

PubMed [citation]

PMID:: 33357406
PMCID:: PMC7820803

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001412453.5

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 43 of the MSH2 protein (p.Tyr43His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 186149). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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