NM_000251.3:c.289C>G

Variant names:

• chr2-47408478-C-G
• rs63750970
• NM_000251.3:c.289C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000251.3(MSH2):​c.289C>G​(p.Gln97Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.84

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-47408478-C-G is Benign according to our data. Variant chr2-47408478-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 945973.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.289C>G	p.Gln97Glu	missense_variant	Exon 2 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.289C>G	p.Gln97Glu	missense_variant	Exon 2 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460012 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726390

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Sep 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 945973). This missense change has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 10612827). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 97 of the MSH2 protein (p.Gln97Glu). -

Hereditary cancer-predisposing syndrome Benign:1

Jun 12, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.60	D;T;.;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N;N;N;.;N
REVEL	Uncertain	0.60
Sift	Benign	0.072	T;D;T;.;T
Sift4G	Benign	0.066	T;D;T;.;T
Polyphen		0.053	B;.;.;.;B
Vest4		0.50
MutPred		0.58		Loss of MoRF binding (P = 0.0286);.;.;Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);
MVP		0.92
MPC		0.011
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.55
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs63750970; hg19: chr2-47635617;