NM_000251.3(MSH2):c.763A>G (p.Ser255Gly) AND Lynch syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 20, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000757937.6

Allele description [Variation Report for NM_000251.3(MSH2):c.763A>G (p.Ser255Gly)]

NM_000251.3(MSH2):c.763A>G (p.Ser255Gly)

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.763A>G (p.Ser255Gly)

HGVS:

NC_000002.12:g.47412531A>G
NG_007110.2:g.14408A>G
NM_000251.3:c.763A>GMANE SELECT
NM_001258281.1:c.565A>G
NP_000242.1:p.Ser255Gly
NP_000242.1:p.Ser255Gly
NP_001245210.1:p.Ser189Gly
LRG_218t1:c.763A>G
LRG_218:g.14408A>G
LRG_218p1:p.Ser255Gly
NC_000002.11:g.47639670A>G
NM_000251.1:c.763A>G
NM_000251.2:c.763A>G

Protein change:

S189G

Links:

dbSNP: rs761529282

NCBI 1000 Genomes Browser:

rs761529282

Molecular consequence:

NM_000251.3:c.763A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.565A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000886466	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Tsai GJ et al. (Genet Med 2018))	Likely benign (May 9, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004829127	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33357406, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000886466

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Tsai GJ et al. (Genet Med 2018))

Likely benign
(May 9, 2018)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV004829127

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 20, 2023)

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	yes	not provided	1	not provided	not provided	no	research
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.

Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, Bowen DJ, Shirts BH.

Genet Med. 2019 Jun;21(6):1435-1442. doi: 10.1038/s41436-018-0335-7. Epub 2018 Oct 30.

PubMed [citation]

PMID:: 30374176

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 University of Washington Department of Laboratory Medicine, University of Washington, SCV000886466.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	no	research	PubMed (1)

Description

The MSH2 variant designated as NM_000251.2: c.763A>G (p.S255G) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (RaÃ±ola et al, 2018, PMID:28965303) and shows a likelihood ratio of 0.08 to 1 that this allele explains cancer in the family (Thompson, et al., 2003, PMID:2900794). Computer software prediction programs also suggest the MSH2 p.S255G change is benign. Additionally, in the observed family, the variant co-occurs with a likely pathogenic variant in the MSH6 gene (p.R1076C). Immunohistochemical studies of endometrial tumor from one family member with the variant showed loss of the MSH6 protein, but no loss of IHC staining for MSH2, which is consistent with the likely pathogenic variant in the MSH6 gene. Together, this information is not consistent with a pathogenic mutation in MSH2. Bayesian analysis integrating data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH2 function or modify risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

#	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	1	not provided

From All of Us Research Program, National Institutes of Health, SCV004829127.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces serine with glycine at codon 255 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). TThis variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine