NM_000251.3(MSH2):c.1811C>G (p.Ala604Gly) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 19, 2024
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:: RCV001358987.6

Allele description [Variation Report for NM_000251.3(MSH2):c.1811C>G (p.Ala604Gly)]

NM_000251.3(MSH2):c.1811C>G (p.Ala604Gly)

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.1811C>G (p.Ala604Gly)

HGVS:

NC_000002.12:g.47475076C>G
NG_007110.2:g.76953C>G
NM_000251.3:c.1811C>GMANE SELECT
NM_001258281.1:c.1613C>G
NP_000242.1:p.Ala604Gly
NP_001245210.1:p.Ala538Gly
LRG_218:g.76953C>G
NC_000002.11:g.47702215C>G
NM_000251.1:c.1811C>G

Protein change:

A538G

Links:

dbSNP: rs2104338716

NCBI 1000 Genomes Browser:

rs2104338716

Molecular consequence:

NM_000251.3:c.1811C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1613C>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
SCV001554847	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 35449176, 21520333, 33357406, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001554847

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 19, 2024)

germline

clinical testing

PubMed (4)
[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

Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients.

Hu L, Sun J, Li Z, Qu Z, Liu Y, Wan Q, Liu J, Ding X, Zang F, Zhang J, Yao L, Xu Y, Wang Y, Xie Y.

NPJ Breast Cancer. 2022 Apr 21;8(1):52. doi: 10.1038/s41523-022-00417-x.

PubMed [citation]

PMID:: 35449176
PMCID:: PMC9023502

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]

PMID:: 21520333

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001554847.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 604 of the MSH2 protein (p.Ala604Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35449176). This missense change has been observed to co-occur in individuals with a different variant in MSH2 that has been determined to be pathogenic (PMID: 21520333), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 1051008). 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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