2-47480871-G-C

Position:

• chr2-47480871-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP3_Strong PP5_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

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47480871-G-C is Pathogenic according to our data. Variant chr2-47480871-G-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 91022.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=3}. Variant chr2-47480871-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2634G>C	p.Glu878Asp	missense_variant, splice_region_variant	15/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2634G>C	p.Glu878Asp	missense_variant, splice_region_variant	15/16	1	NM_000251.3	P1

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

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 01, 2019	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 14, 2022	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 09, 2023

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

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 04, 2019

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. This variant is not present in population databases (ExAC no frequency). 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). Experimental studies have shown that this missense change results in reduced MSH2 protein levels and high microsatellite slippage (PMID: 26951660). 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. 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. For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 13, 2018

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

Computational scores

Source: dbNSFP v4.3

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;D;T;T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	2.0	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N;.;N
REVEL	Uncertain	0.55
Sift	Benign	0.060	T;T;.;T
Sift4G	Benign	0.24	T;T;.;T
Polyphen		0.35	B;.;.;D
Vest4		0.49
MutPred		0.70		Loss of disorder (P = 0.086);.;Loss of disorder (P = 0.086);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs63751624; hg19: chr2-47708010;