2-47476451-G-T

Variant names:

• chr2-47476451-G-T
• rs63750398
• NM_000251.3:c.2090G>T

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.2090G>T​(p.Cys697Phe) 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. C697R) 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:4
• Conservation: PhyloP100: 9.60

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 8) in uniprot entity MSH2_HUMAN there are 7 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 chr2-47476450-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 2-47476451-G-T is Pathogenic according to our data. 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. Variant chr2-47476451-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2090G>T	p.Cys697Phe	missense_variant	Exon 13 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2090G>T	p.Cys697Phe	missense_variant	Exon 13 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Jul 03, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with phenylalanine at codon 697 of the MSH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes deficient mismatch repair activity, reduced protein expression, and abnormal cellular localization (PMID: 10469597, 16327991, 17101317, 17720936, 18822302, 18951462, 22102614). This variant has been reported in more than 10 individuals affected with colorectal cancer, endometrial cancer, and sebaceous carcinoma (PMID: 10323887, 11231323, 11859205, 12436451, 15235030, 16327991, 17101317, 18566915, 9298827). Microsatellite instability has been demonstrated in more than 5 tumor samples from these individuals (PMID: 11231323, 11859205, 12436451, 16327991, 17101317). Immunohistochemistry has demonstrated loss of MSH2 protein expression in more than 5 tumor samples (PMID: 11859205, 12436451, 15235030, 16327991, 17101317). Different variants affecting the same position (p.Cys697Tyr and p.Cys697Arg) are considered to be disease-causing (ClinVar variation ID: 187518 and 90882), suggesting that cysteine at this position is important for protein structure and function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Mar 02, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C697F pathogenic mutation (also known as c.2090G>T), located in coding exon 13 of the MSH2 gene, results from a G to T substitution at nucleotide position 2090. The cysteine at codon 697 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been found to have moderate segregation with disease in families that met Amsterdam criteria for Lynch syndrome. Tumor samples from at least one affected individual in each family demonstrated high microsatellite instability (Wehner M et al. Hum. Mutat., 1997;10:241-4; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17; Ollila S et al. Int. J. Oncol., 2006 Jan;28:149-53). Several studies performed with this variant demonstrated reduced mismatch repair activity when compared to wild type and defective DNA mismatch binding (Ollila S et al. Int. J. Oncol., 2006 Jan;28:149-53; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17; Drost M et al. Hum. Mutat., 2012 Mar;33:488-94; Lützen A et al. Mutat. Res., 2008 Oct;645:44-55; Ollila S et al. Hum. Mutat., 2008 Nov;29:1355-63). This alteration has also been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Nat. Genet., 2014 Feb;46:107-15). The p.C697F alteration is part of the ATPase domain, which is a structurally important region (Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). Based on internal structural analysis, this variant is significantly more destabilizing than nearby known pathogenic variants (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. -

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 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Aug 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 697 of the MSH2 protein (p.Cys697Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 9298827, 16327991, 17101317). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90883). 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. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 18951462, 22102614). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.8	H;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-9.4	D;D;.;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.97
MutPred		0.96		Loss of catalytic residue at P696 (P = 0.012);.;Loss of catalytic residue at P696 (P = 0.012);Loss of catalytic residue at P696 (P = 0.012);
MVP		0.96
MPC		0.030
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs63750398; hg19: chr2-47703590;