NM_000251.3(MSH2):c.814G>A (p.Ala272Thr) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 19, 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:: RCV001869152.5

Allele description [Variation Report for NM_000251.3(MSH2):c.814G>A (p.Ala272Thr)]

NM_000251.3(MSH2):c.814G>A (p.Ala272Thr)

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.814G>A (p.Ala272Thr)

HGVS:

NC_000002.12:g.47414290G>A
NG_007110.2:g.16167G>A
NM_000251.3:c.814G>AMANE SELECT
NM_001258281.1:c.616G>A
NP_000242.1:p.Ala272Thr
NP_001245210.1:p.Ala206Thr
LRG_218:g.16167G>A
NC_000002.11:g.47641429G>A
NM_000251.1:c.814G>A

Protein change:

A206T

Links:

dbSNP: rs1558463956

NCBI 1000 Genomes Browser:

rs1558463956

Molecular consequence:

NM_000251.3:c.814G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.616G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Small ubiquitin-related modifier 2 [Heterocephalus glaber]
Small ubiquitin-related modifier 2 [Heterocephalus glaber]
gi|351702606|gb|EHB05525.1||gnl|WGS |GW7_11420

Protein
transmembrane protein 32 (predicted) [Rattus norvegicus]
transmembrane protein 32 (predicted) [Rattus norvegicus]
gi|149015823|gb|EDL75147.1||gnl|WGS |rCP10230

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002173071	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 33357406, 33646313, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002173071

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 19, 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

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

Gene Sequencing for Pathogenic Variants Among Adults With Breast and Ovarian Cancer in the Caribbean.

George SHL, Donenberg T, Alexis C, DeGennaro V Jr, Dyer H, Yin S, Ali J, Butler R, Chin SN, Curling D, Lowe D, Lunn J, Turnquest T, Wharfe G, Cerbon D, Barreto-Coelho P, Schlumbrecht MP, Akbari MR, Narod SA, Hurley JE.

JAMA Netw Open. 2021 Mar 1;4(3):e210307. doi: 10.1001/jamanetworkopen.2021.0307.

PubMed [citation]

PMID:: 33646313
PMCID:: PMC7921902

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002173071.3

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

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 632900). This missense change has been observed in individual(s) with breast cancer (PMID: 33646313). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 272 of the MSH2 protein (p.Ala272Thr).

#	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: May 1, 2024

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