NM_000251.3:c.868G>C

Variant names:

• chr2-47414344-G-C
• rs587779190
• NM_000251.3:c.868G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000251.3(MSH2):​c.868G>C​(p.Glu290Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,412,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. E290D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.40
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29200262).

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.868G>C	p.Glu290Gln	missense	Exon 5 of 16	NP_000242.1
	MSH2	NM_001406674.1		c.868G>C	p.Glu290Gln	missense	Exon 5 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.868G>C	p.Glu290Gln	missense	Exon 5 of 18	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.868G>C	p.Glu290Gln	missense	Exon 5 of 16	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.868G>C	p.Glu290Gln	missense	Exon 5 of 16	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.868G>C	p.Glu290Gln	missense	Exon 5 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251232 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1412916 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 701698

African (AFR) AF: 0.00 AC: 0 AN: 32260

American (AMR) AF: 0.00 AC: 0 AN: 43026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24308

East Asian (EAS) AF: 0.00 AC: 0 AN: 36012

South Asian (SAS) AF: 0.00 AC: 0 AN: 85744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1079226

Other (OTH) AF: 0.00 AC: 0 AN: 57142

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 290 of the MSH2 protein (p.Glu290Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Benign	0.17
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.095
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Benign	0.61	N
PhyloP100		7.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.020	N
REVEL	Uncertain	0.48
Sift	Benign	1.0	T
Sift4G	Benign	0.76	T
Polyphen		0.045	B
Vest4		0.65
MutPred		0.39		Loss of catalytic residue at E290 (P = 0.0674)
MVP		0.93
MPC		0.0073
ClinPred		0.48	T
GERP RS		5.1
Varity_R		0.26
gMVP		0.18
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs587779190; hg19: chr2-47641483;