rs1114167857

Variant names:

• chr2-47476442-T-C
• rs1114167857
• NM_000251.3:c.2081T>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.2081T>C​(p.Phe694Ser) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 2-47476442-T-C is Pathogenic according to our data. Variant chr2-47476442-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47476442-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2081T>C	p.Phe694Ser	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.2081T>C	p.Phe694Ser	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/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome Pathogenic:1

Apr 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces phenylalanine with serine at codon 694 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 a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406), and has demonstrated defective mismatch repair activity compared to wild type protein (PMID: 27629256). This variant has been reported in individuals affected with Lynch syndrome-associated cancer, with multiple tumors demonstrating high microsatellite instability and/or loss of MSH2/MSH6 protein via immunohistochemistry (PMID: 21156417, 27629256; ClinVar SCV000580570.5). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2080T>A (p.Phe694Ile), is considered to be disease-causing (ClinVar variation ID: 820674), suggesting that this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 694 of the MSH2 protein (p.Phe694Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 21156417; internal data). ClinVar contains an entry for this variant (Variation ID: 428522). Invitae Evidence Modeling incorporating data from in vitro 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: 27629256). 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

Jan 22, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F694S variant (also known as c.2081T>C), located in coding exon 13 of the MSH2 gene, results from a T to C substitution at nucleotide position 2081. The phenylalanine at codon 694 is replaced by serine, an amino acid with highly dissimilar properties. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2 and MSH6 expression by immunohistochemistry (IHC) (Ambry internal data). This alteration was also identified in an individual from Northern Spain who was diagnosed with colorectal cancer at age 44 and whose tumor demonstrated loss of both MSH2 and MSH6 expression on IHC (Zarate R et al. Clin. Transl. Oncol. 2010 Dec;12(12):849-51). Additionally, this alteration was identified in an individual diagnosed with endometrial cancer whose family history met Amsterdam criteria for Lynch syndrome. Tumor results for this proband revealed microsatellite instability (MSI-H) and absence of both MSH2 and MSH6 staining on IHC (Tricarico R et al. Hum. Mutat. 2017 01;38:64-77). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

MSH2, EXON13, c.2081T>C, p.Phe694Ser, Heterozygous, Uncertain Significance The MSH2 p.Phe694Ser variant was identified in the literature in a study assessing the RNA effects, protein expression levels, and in vitro MMR activity; the variant found to have no splicing defects, but did decrease MMR activity; in addition, segregation studies determined the variant cosegregated with disease (Tricarico 2017). The variant was also identified in Insight Hereditary Tumors Database (2 x, as class 5) database. The variant was not identified in dbSNP, ClinVar, GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, MMR Gene Unclassified Variants Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Phe694 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the DNA mismatch repair protein MutS, C-terminal P-loop containing nucleoside triphosphate hydrolase DNA mismatch repair protein, MSH2 functional domain(s) increasing the likelihood that it may have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. REFERENCES: Tricarico R, Kasela M, Mareni C, Thompson BA, Drouet A, Staderini L, Gorelli G, Crucianelli F, Ingrosso V, Kantelinen J, Papi L, De Angioletti M, Berardi M, Gaildrat P, Soukarieh O, Turchetti D, Martins A, Spurdle AB, Nyström M, Genuardi M; InSiGHT Variant Interpretation Committee.. Assessment of the InSiGHT Interpretation Criteria for the Clinical Classification of 24 MLH1 and MSH2 Gene Variants. Hum Mutat. 2017 Jan;38(1):64-77. doi: 10.1002/humu.23117. Epub 2016 Oct 17. PubMed PMID: 27629256. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.6	D;D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.98
MutPred		0.89		Loss of catalytic residue at F694 (P = 0.2764);.;Loss of catalytic residue at F694 (P = 0.2764);Loss of catalytic residue at F694 (P = 0.2764);
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		0.98
gMVP		0.98

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: rs1114167857; hg19: chr2-47703581;