NM_000251.3(MSH2):c.2021G>A (p.Gly674Asp) AND Lynch syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 21, 2019
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:: RCV000076363.4

Allele description [Variation Report for NM_000251.3(MSH2):c.2021G>A (p.Gly674Asp)]

NM_000251.3(MSH2):c.2021G>A (p.Gly674Asp)

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.2021G>A (p.Gly674Asp)

HGVS:

NC_000002.12:g.47476382G>A
NG_007110.2:g.78259G>A
NM_000251.3:c.2021G>AMANE SELECT
NM_001258281.1:c.1823G>A
NP_000242.1:p.Gly674Asp
NP_000242.1:p.Gly674Asp
NP_001245210.1:p.Gly608Asp
LRG_218t1:c.2021G>A
LRG_218:g.78259G>A
LRG_218p1:p.Gly674Asp
NC_000002.11:g.47703521G>A
NM_000251.1:c.2021G>A
NM_000251.2:c.2021G>A

Protein change:

G608D

Links:

dbSNP: rs267607996

NCBI 1000 Genomes Browser:

rs267607996

Molecular consequence:

NM_000251.3:c.2021G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1823G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000107390	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v2.4)	Likely pathogenic (Jun 21, 2019)	germline	curation	Citation Link,
SCV000917714	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 13, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10523644, 28932927, 29575718, 11601928, 12875840, 21598002, 17720936, 12624141 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000107390

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v2.4)

Likely pathogenic
(Jun 21, 2019)

germline

curation

Citation Link,

SCV000917714

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 13, 2018)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

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

Citations

PubMed

Separation-of-function mutations in Saccharomyces cerevisiae MSH2 that confer mismatch repair defects but do not affect nonhomologous-tail removal during recombination.

Studamire B, Price G, Sugawara N, Haber JE, Alani E.

Mol Cell Biol. 1999 Nov;19(11):7558-67.

PubMed [citation]

PMID:: 10523644
PMCID:: PMC84769

Screening for germline mutations in mismatch repair genes in patients with Lynch syndrome by next generation sequencing.

Soares BL, Brant AC, Gomes R, Pastor T, Schneider NB, Ribeiro-Dos-Santos Â, de Assumpção PP, Achatz MIW, Ashton-Prolla P, Moreira MAM.

Fam Cancer. 2018 Jul;17(3):387-394. doi: 10.1007/s10689-017-0043-5.

PubMed [citation]

PMID:: 28932927

See all PubMed Citations (8)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000107390.3

#	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 0.95-0.99

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917714.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: MSH2 c.2021G>A (p.Gly674Asp) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246190 control chromosomes. c.2021G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome, including cosegregation with disease in one family (Parc_2003). In addition, several other variants at the same codon (p.G674A, p.G674R, and p.G674S) are reported as being associated with colorectal cancer, suggesting it is important for protein function. These data indicate that the variant is likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. Although protein:protein interactions such as MSH2-MSH6 binding were not affected by the variant (Gammie_2007), MMR function was found to be defective and ATP-mediated dissocation in the presence of mismatch DNA was also impaired (Gammie_2007; Kijas_2003). Overall, the most pronounced variant effect in these functional studies results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Jun 9, 2024

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