2-47480871-G-C

Variant names:

• chr2-47480871-G-C
• rs63751624
• NM_000251.3:c.2634G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000251.3(MSH2):​c.2634G>C​(p.Glu878Asp) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E878Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 8.65
• Publications: 7 publications found

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]

MSH2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.2634G>C	p.Glu878Asp	missense splice_region	Exon 15 of 16	NP_000242.1
	MSH2	NM_001406653.1		c.2574G>C	p.Glu858Asp	missense	Exon 15 of 15	NP_001393582.1
	MSH2	NM_001406674.1		c.2634G>C	p.Glu878Asp	missense splice_region	Exon 15 of 18	NP_001393603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.2634G>C	p.Glu878Asp	missense splice_region	Exon 15 of 16	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.2634G>C	p.Glu878Asp	missense splice_region	Exon 15 of 16	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.2634G>C	p.Glu878Asp	missense splice_region	Exon 15 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:7 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 01, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2634G>C variant (also known as p.E878D), located in coding exon 15 of the MSH2 gene, results from a G to C substitution at nucleotide position 2634. The amino acid change results in glutamic acid to aspartic acid at codon 878, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This alteration has been detected in multiple Lynch syndrome patients meeting Amsterdam or Bethesda criteria and the tumor of one of these patients demonstrated high microsatellite instability and absent MSH2 protein expression on immunohistochemistry (Terdiman JP et al. Gastroenterology. 2001 Jan;120(1):21-30; Nilbert M et al. Fam Cancer. 2009;8(1):75-83). In addition, a splicing assay performed on an alteration at the same nucleotide position (c.2634G>A) demonstrated aberrant splicing and a functional assay performed on another alteration at the same nucleotide position (c.2634G>T) demonstrated attenuated MMR capacity (Pérez-Cabornero L et al. J Mol Diagn, 2013 May;15:380-90; Houlleberghs H et al. Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):4128-33). Based on the available evidence, c.2634G>C is classified as a pathogenic mutation.

Mar 14, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant changes the last nucleotide of exon 15 of the MSH2 gene, replacing a glutamine with aspartate, and is predicted to impair RNA splicing. RNA studies with carrier individuals have shown that this variant cause skipping of exon 15, and is predicted to result in a frameshift and premature truncation (PMID: 23523604, 26951660). This variant has been reported in individuals affected with Lynch syndrome (PMID: 11208710, 23523604, 25648859). 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 Likely Pathogenic.

Lynch syndrome 1 Pathogenic:1

Aug 09, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 23523604].

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jun 04, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 878 of the MSH2 protein (p.Glu878Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant also falls at the last nucleotide of exon 15 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. For these reasons, this variant has been classified as Pathogenic. A different variant affecting this nucleotide (c.2634G>A) has been determined to be pathogenic (PMID: 23523604, 21778331, 21791569). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this missense change results in reduced MSH2 protein levels and high microsatellite slippage (PMID: 26951660). This variant has been observed in several individuals suspected of having Lynch syndrome (PMID: 18566915, 11208710, 25648859). It has also been observed to segregate with Lynch syndrome-associated cancers in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 91022).

Lynch syndrome Uncertain:1

Jun 13, 2018

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

G>non-G at last base of exon with first 6 intronic bases not GTRRGT; Insufficient evidence

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	2.0	M
PhyloP100		8.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.55
Sift	Benign	0.060	T
Sift4G	Benign	0.24	T
Polyphen		0.35	B
Vest4		0.49
MutPred		0.70		Loss of disorder (P = 0.086)
MVP		0.97
MPC		0.0072
ClinPred		0.94	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.33
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: 4
DS_DL_spliceai		0.76		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs63751624; hg19: chr2-47708010;