rs63751110

Positions:

• chr2-47410322-T-C
• chr2-47410322-T-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.595T>C​(p.Cys199Arg) 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. 12/21 in silico tools predict a damaging 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. C199Y) 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:4
• 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 6 pathogenic changes around while only 1 benign (86%) 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 chr2-47410323-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 2-47410322-T-C is Pathogenic according to our data. Variant chr2-47410322-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 91146.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47410322-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.595T>C	p.Cys199Arg	missense_variant	3/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.595T>C	p.Cys199Arg	missense_variant	3/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

The p.C199R variant (also known as c.595T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 595. The cysteine at codon 199 is replaced by arginine, an amino acid with highly dissimilar properties. Two other alterations at the same amino acid position, p.C199Y and p.C199W, have been reported as likely pathogenic. This variant was not reported in populationbased cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In-silico prediction show pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs no benign predictions. Therefore, this variant has been classified as pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability >0.99 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 199 of the MSH2 protein (p.Cys199Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 9777949, 12386821, 18561205). ClinVar contains an entry for this variant (Variation ID: 91146). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936, 28422960, 29731845, 30998989, 31237724). This variant disrupts the p,Cys199 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17440950). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2024

The p.C199R pathogenic mutation (also known as c.595T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 595. The cysteine at codon 199 is replaced by arginine, an amino acid with highly dissimilar properties. In one study, this alteration was detected in an individual diagnosed with rectal cancer at 28 years of age and a glioblastoma at 37 and whose tumor demonstrated high microsatellite instability and absent staining of MSH2 by immunohistochemistry (IHC). In addition, this individual had a reported family history significant for 2 sisters diagnosed with colorectal cancer, one of which underwent testing and was also found to have the p.C199R alteration (Leung SY et al. Am J Pathol. 1998;153(4):1181-8; Chan TL et al. J. Natl. Cancer Inst., 1999 Jul;91:1221-6). In a separate study, functional assays in yeast demonstrated that the p.C199R (p.C195R in yeast) alteration resulted in a reduction of MSH2 levels to 2% of wild-type, inhibited mismatch repair activity, and destabilized protein subunit interactions. Based on the 3D protein structures provided in this publication, codon 199 (195 in yeast) is crucial for proper interaction between domains 1 and 2 in the inner core (Gammie AE et al. Genetics. 2007;177(2):707-21). Another functional study demonstrated that C199R has reduced nuclear localization compared to the wild type (Nielsen SV et al. PLoS Genet., 2017 Apr;13:e1006739). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-10	D;D;D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;.;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.99
MutPred		0.96		Gain of disorder (P = 0.0161);.;.;Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);
MVP		0.98
MPC		0.028
ClinPred		1.0	D
GERP RS		5.7
Varity_R		1.0
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs63751110; hg19: chr2-47637461; COSMIC: COSV51886224;