2-47410245-T-G

Variant names:

• chr2-47410245-T-G
• rs63750070
• NM_000251.3:c.518T>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.518T>G​(p.Leu173Arg) 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. L173P) 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:3
• 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 strand (size 7) in uniprot entity MSH2_HUMAN there are 5 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 chr2-47410245-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 2-47410245-T-G is Pathogenic according to our data. Variant chr2-47410245-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 91122.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47410245-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.518T>G	p.Leu173Arg	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.518T>G	p.Leu173Arg	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:3

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Mar 09, 2018

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Class 5 - Pathogenic Classification using multifactorial probability: 0.993 -

Lynch syndrome Pathogenic:1

Jan 30, 2019

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 16, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2_Supporting, PP1_Moderate, PP3_Moderate, PP4_Strong c.518T>G, located in exon 3 of the MSH2 gene, is predicted to result in the substitution of leucine by arginine at codon 173, p.(Leu173Arg). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). Computational tools predict a deleterious effect of the variant on protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.95) (PP3_Moderate). A functional study based on cell viability assay in HEK293 or HAP1 cells using 6-TG treatment demonstrates abnormal function for this variant, with a LOF score 3.52 (PMID: 33357406) (PS3). It has been reported in 5 CRC or EC tumors with loss of MSH2/MSH6 protein expression consistent with the variant location and, moreover, one of them presented MSI-H too (PMID: 28577310; and one case from our clinical cohort of patients) (PP4_Strong). The variant cosegregates with the disease in 6 individuals from three different families (internal data; PP1_Moderate). In addition, the variant was also identified in the following databases: InSiGHT (Class 5 - Pathogenic Classification using multifactorial probability: 0.993), ClinVar (2x pathogenic), LOVD (11x pathogenic). Based on the currently available information, c.518T>G is classified as a pathogenic variant according to ClinGen-MMR Guidelines Draft version v3.1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.9	D;D;D;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;.;D
Polyphen		0.99	D;.;.;.;D
Vest4		0.92
MutPred		0.93		Gain of ubiquitination at K172 (P = 0.0522);.;.;Gain of ubiquitination at K172 (P = 0.0522);Gain of ubiquitination at K172 (P = 0.0522);
MVP		0.99
MPC		0.029
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.92

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: rs63750070; hg19: chr2-47637384;