NM_000251.3(MSH2):c.2060T>C (p.Leu687Pro) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 30, 2021
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:: RCV000586744.8

Allele description [Variation Report for NM_000251.3(MSH2):c.2060T>C (p.Leu687Pro)]

NM_000251.3(MSH2):c.2060T>C (p.Leu687Pro)

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.2060T>C (p.Leu687Pro)

Other names:

p.L687P:CTC>CCC

HGVS:

NC_000002.12:g.47476421T>C
NG_007110.2:g.78298T>C
NM_000251.3:c.2060T>CMANE SELECT
NM_001258281.1:c.1862T>C
NP_000242.1:p.Leu687Pro
NP_000242.1:p.Leu687Pro
NP_001245210.1:p.Leu621Pro
LRG_218t1:c.2060T>C
LRG_218:g.78298T>C
LRG_218p1:p.Leu687Pro
NC_000002.11:g.47703560T>C
NM_000251.1:c.2060T>C
NM_000251.2:c.2060T>C
p.L687P

Protein change:

L621P

Links:

dbSNP: rs587779133

NCBI 1000 Genomes Browser:

rs587779133

Molecular consequence:

NM_000251.3:c.2060T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1862T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002047290	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Mar 30, 2021)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 28514183, 17531815, 24603434, 22290698, 20459533, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002047290

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Likely pathogenic
(Mar 30, 2021)

unknown

clinical testing

PubMed (6)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Multigene Panel Testing Provides a New Perspective on Lynch Syndrome.

Espenschied CR, LaDuca H, Li S, McFarland R, Gau CL, Hampel H.

J Clin Oncol. 2017 Aug 1;35(22):2568-2575. doi: 10.1200/JCO.2016.71.9260. Epub 2017 May 17.

PubMed [citation]

PMID:: 28514183
PMCID:: PMC7186580

Structure of the human MutSalpha DNA lesion recognition complex.

Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS.

Mol Cell. 2007 May 25;26(4):579-92.

PubMed [citation]

PMID:: 17531815

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000211196.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is denoted MSH2 c.2060T>C at the cDNA level, p.Leu687Pro (L687P) at the protein level, and results in the change of a Leucine to a Proline (CTC>CCC). This variant was observed in two tumors of the large intestine; however, it was not determined whether these variants were somatic or germline (COSMIC). MSH2 Leu687Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Leu687Pro occurs at a position that is highly conserved across species and is located in the ATPase domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Leu687Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002047290.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The variant has been reported as a variant of uncertain significance based on immunohistochemical analysis of colorectal tumor samples from Lynch syndrome patients in the published literature (PMID 20459533 (2010)). This variant was also identified in an individual with Muir–Torre syndrome or in individuals undergoing multigene cancer panel testing (PMID: 24603434 (2014), 28514183 (2017)). Furthermore, this variant was found to segregate with MSH2-related cancers in one family tested internally. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211196	GeneDx	flagged submission Reason: Older claim that does not account for recent evidence Notes: None (GeneDx Variant Classification (06012015))	Uncertain significance (Mar 8, 2017)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000211196

GeneDx

flagged submission

Reason: Older claim that does not account for recent evidence

Notes: None

(GeneDx Variant Classification (06012015))

Uncertain significance
(Mar 8, 2017)

germline

clinical testing

Citation Link

Last Updated: Sep 29, 2024

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