2-47476450-T-C

Position:

• chr2-47476450-T-C

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.2089T>C​(p.Cys697Arg) 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. C697F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.67

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 hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 15 uncertain 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 chr2-47476451-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 90883.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-47476450-T-C is Pathogenic according to our data. Variant chr2-47476450-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 90882.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476450-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2089T>C	p.Cys697Arg	missense_variant	13/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2089T>C	p.Cys697Arg	missense_variant	13/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces cysteine with arginine at codon 697 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). This variant impacts MSH2 function in 6-thioguanine sensitivity assays (PMID: 26951660, 33357406). This variant has been reported in individuals and families affected with Lynch syndrome and Lynch syndrome-associated disease (PMID: 10480359, 10612836, 14970868, 17973265, 20937110, 21239990, 21598002). It has been described that this variant segregates with disease (PMID: 10612836). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.2090G>T (p.Cys697Phe), c.2090G>A (p.Cys697Tyr), c.2090G>C (p.Cys697Ser), and c.2091T>G (p.Cys697Trp) are considered to be disease-causing (ClinVar variation ID: 90883, 187518, 856441, 2453475), suggesting that this position is important for the protein function. Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Multifactorial likelihood analysis posterior probability >0.99 -

MSH2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2023

The MSH2 c.2089T>C variant is predicted to result in the amino acid substitution p.Cys697Arg. This variant has been reported in individuals with Lynch syndrome (Table 1, Wang et al. 1999. PubMed ID: 10480359; Table 1, Ponz de Leon et al. 2004. PubMed ID: 14970868; Table 1, Yoon et al. 2008. PubMed ID: 17973265; Table 2, Thodi et al. 2010. PubMed ID: 20937110; Table 3, Pastrello et al. 2011. PubMed ID: 21239990). The results of in vitro and in vivo experimental studies suggest this variant impacts protein function (Figures 2, 4, and 6, Brieger et al. 2002. PubMed ID: 12377806; Table 2, Gammie et al. 2007. PubMed ID: 17720936; Table S1, Bouvet et al. 2019. PubMed ID: 30998989; Table 2, Rath et al. 2019. PubMed ID: 31237724). This variant is predicted to be pathogenic by mismatch repair (MMR) gene and other in silico tools (Table 4, Pastrello et al. 2011. PubMed ID: 21239990; Table 3, Ali et al. 2012. PubMed ID: 22290698; Table 2, Thompson et al. 2013. PubMed ID: 22949387). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating that it is rare. It is interpreted as pathogenic in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/90882). An alternate nucleotide change affecting the same amino acid (p.Cys697Phe) has been associated with Lynch syndrome and interpreted as pathogenic in ClinVar (Table 1, Wehner et al. 1997. PubMed ID: 9298827; Table 1, Ollila et al. 2006. PubMed ID: 17101317; Table 1, Ollila et al. 2008. PubMed ID: 18951462; https://preview.ncbi.nlm.nih.gov/clinvar/variation/90883/). The c.2089T>C (p.Cys697Arg) variant is interpreted as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 697 of the MSH2 protein (p.Cys697Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary nonpolyposis colorectal cancer (PMID: 10471663, 10480359, 10612836, 14970868, 17973265, 20937110, 21239990, 21598002). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90882). 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: 12377806, 17720936). This variant disrupts the p.Cys697 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9298827, 17101317, 18951462, 21239990). 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

Jan 29, 2018

The p.C697R pathogenic mutation (also known as c.2089T>C), located in coding exon 13 of the MSH2 gene, results from a T to C substitution at nucleotide position 2089. The cysteine at codon 697 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch syndrome, and has been shows to segregate with disease in multiple large families (Wang Q et al. Hum. Genet.; 1999 105:79-85; Isidro G et al. Hum. Mutat., 2000 Jan;15:116; Brieger A et al. Gut, 2002 Nov;51:677-84; Ponz de Leon M et al. Br. J. Cancer, 2004 Feb;90:882-7; Yoon SN et al. Int. J. Cancer, 2008 Mar;122:1077-81; Thodi G et al. BMC Cancer, 2010 Oct;10:544; Pastrello C et al. Genet. Med., 2011 Feb;13:115-24). A functional study using a cDNA-mutant construct showed this alteration has a deleterious effect on mismatch repair function (Brieger A et al. Gut, 2002 Nov;51:677-84). An additional functional analysis using the yeast homolog, msh2-C716R, has shown this alteration results in only 5% relative yeast Msh2 expression (Gammie AE et al. Genetics, 2007 Oct;177:707-21). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). 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 available evidence, p.C697R is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.8	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-10	D;D;.;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.98		Loss of catalytic residue at P696 (P = 0.0079);.;Loss of catalytic residue at P696 (P = 0.0079);Loss of catalytic residue at P696 (P = 0.0079);
MVP		0.96
MPC		0.028
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99

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: rs63750961; hg19: chr2-47703589;