2-47410287-T-G

Variant names:

• chr2-47410287-T-G
• rs63751444
• NM_000251.3:c.560T>G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.560T>G​(p.Leu187Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L187P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.96

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a helix (size 9) in uniprot entity MSH2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47410287-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 2-47410287-T-G is Pathogenic according to our data. Variant chr2-47410287-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 91135.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47410287-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.560T>G	p.Leu187Arg	missense_variant	Exon 3 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.560T>G	p.Leu187Arg	missense_variant	Exon 3 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Jul 27, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 19697156, 26951660, 16327991, 17101317]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19697156]. -

Lynch syndrome Pathogenic:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability >0.99 -

not provided Pathogenic:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jul 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with arginine at codon 187 of the MSH2 protein (p.Leu187Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several families affected with Lynch syndrome-associated cancers (PMID: 12624141, 21642682, 16395668, 19697156, 10995807). ClinVar contains an entry for this variant (Variation ID: 91135). Experimental studies have shown that this missense change impairs the mismatch repair activity of the MSH2 protein (PMID: 26951660, 19697156). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Variants that disrupt the p.Leu187 amino acid residue in MSH2 have been observed in affected individuals (PMID: 18951462, 16327991, 28422960, 17101317, 26951660). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 18, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L187R variant (also known as c.560T>G), located in coding exon 3 of the MSH2 gene, results from a T to G substitution at nucleotide position 560. The leucine at codon 187 is replaced by arginine, an amino acid with dissimilar properties. This alteration is observed in an individual whose colorectal tumor demonstrated high microsatellite instability and loss of MSH2/MSH6 expression on immunohistochemistry (IHC), and family history met Amsterdam criteria (Christensen LL et al. Fam Cancer, 2009 Aug;8:489-500). This alteration is also observed in an individual whose colorectal tumor demonstrated high microsatellite instability and in 2/537 French Lynch syndrome families (Peel DJ et al. J Natl Cancer Inst, 2000 Sep;92:1517-22; Bonadona V et al. JAMA, 2011 Jun;305:2304-10). Functional assays demonstrated deficient MMR activity for p.L187R compared to wild-type MSH2 (Drost M et al. Genet Med, 2019 07;21:1486-1496). Based on internal structural analysis using published crystal structures, L187R disrupts the structure of the MSH6 MutS domain II (Ambry internal data; Warren JJ et al. Mol Cell, 2007 May;26:579-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.9	D;D;D;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D;D;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;.;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.98
MutPred		0.91		Gain of disorder (P = 0.0776);.;.;Gain of disorder (P = 0.0776);Gain of disorder (P = 0.0776);
MVP		0.98
MPC		0.030
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63751444; hg19: chr2-47637426;