NM_000251.3:c.138C>G

Variant names:

• chr2-47403329-C-G
• rs33946261
• NM_000251.3:c.138C>G
• MSH2 p.His46Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025). O6_SupportingB2_Supporting

The NM_000251.3(MSH2):c.138C>G (p.His46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene MSH2 is a tumor suppressor gene (CancerMine: 4 TSG, 3 oncogene, 1 driver citations). The gene MSH2 is a known oncogene (CancerMine: 4 TSG, 3 oncogene, 1 driver citations). The gene MSH2 is a cancer driver gene (CancerMine: 4 TSG, 3 oncogene, 1 driver citations). The variant allele was found at a cumulative frequency of 0.000441 (AC=709) in the gnomAD database across 1,606,276 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000539. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.H46D: Uncertain_significance (ClinVar VariationId 1058599, 1 star); p.H46= (synonymous): Benign/Likely_benign (ClinVar VariationId 491770, 2 stars); p.H46P: Uncertain_significance (ClinVar VariationId 525765, 2 stars); p.H46Q: Benign (ClinVar VariationId 3772757, 1 star); p.H46Y: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 483663) The variant has been observed in cBioPortal in 1 sample across 1 study and 1 cancer type; somatic enrichment level: NONE (Observed in at most one deduplicated cBioPortal case.). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:20 O:1
• Conservation: PhyloP100: 2.26
• Publications: 21 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: ClinGen, G2P, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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: G2P, Labcorp Genetics (formerly Invitae)
• Muir-Torre syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• 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

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	B2Does not fit gene mode of action		Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context); Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MSH2 NM_000251.3	MANE Select	c.138C>G p.His46Gln	missense	Exon 1 of 16	Prot: NP_000242.1 UniProt:
	MSH2 NM_001406674.1		c.138C>G p.His46Gln	missense	Exon 1 of 18	Prot: NP_001393603.1
	MSH2 NM_001406631.1		c.138C>G p.His46Gln	missense	Exon 1 of 18	Prot: NP_001393560.1

MSH2 NM_000251.3

MANE Select

HGVSc / HGVSpc.138C>Gp.His46Gln

Exon rankExon 1 of 16

missense

Prot: NP_000242.1UniProt: P43246-1

MSH2 NM_001406674.1

HGVSc / HGVSpc.138C>Gp.His46Gln

Exon rankExon 1 of 18

missense

Prot: NP_001393603.1

MSH2 NM_001406631.1

HGVSc / HGVSpc.138C>Gp.His46Gln

Exon rankExon 1 of 18

missense

Prot: NP_001393560.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MSH2 ENST00000233146.7	TSL:1MANE Select	c.138C>G p.His46Gln	missense	Exon 1 of 16	Prot: ENSP00000233146.2 UniProt:
	MSH2 ENST00000406134.5	TSL:1	c.138C>G p.His46Gln	missense	Exon 1 of 16	Prot: ENSP00000384199.1 UniProt:
	MSH2 ENST00000918107.1		c.138C>G p.His46Gln	missense	Exon 1 of 17	Prot: ENSP00000588166.1 UniProt:

MSH2 ENST00000233146.7

TSL:1MANE Select

HGVSc / HGVSpc.138C>Gp.His46Gln

Exon rankExon 1 of 16

missense

Prot: ENSP00000233146.2UniProt: P43246-1

MSH2 ENST00000406134.5

TSL:1

HGVSc / HGVSpc.138C>Gp.His46Gln

Exon rankExon 1 of 16

missense

Prot: ENSP00000384199.1UniProt: E9PHA6

MSH2 ENST00000918107.1

HGVSc / HGVSpc.138C>Gp.His46Gln

Exon rankExon 1 of 17

missense

Prot: ENSP00000588166.1UniProt: A0ACI8SWY1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000217	AC:33	Hom:0	AN:152252	Cov:33
GnomAD2 exomes	AF: 0.000218	AC:50	Hom:	AN:229550	Cov:
GnomAD4 exome	AF: 0.000465	AC:676	Hom:0	AN:1454024	Cov:31
GnomAD4 genome	AF: 0.000217	AC:33	Hom:0	AN:152252	Cov:33
TOPMed (Bravo)	AF: 0.000257	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000272	AC:13	Hom:0	AN:47750	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000854	AC:2	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000231	AC:3	Hom:	AN:12966	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000522 *	5	9584	0.000385 *	4	10388
BipEx(Bipolar disorder (including schizoaffective))	0.000387	11	28420	0.000243	7	28844
Epi25(Epilepsy)	0.000381	16	41958	0.000478	32	66888
SCHEMA(Schizophrenia)	0.000165	20	120994	0.000244	46	188366

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	Lynch syndrome 1 (4)
-	-	4	not provided (4)
-	1	3	not specified (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	Lynch syndrome (3)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	Colorectal cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	MSH2-related disorder (1)
-	-	1	Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-8.6
GPN-Star score	N/A	8.6
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.89	D
Mutation Taster	N/A	93/7	polymorphism
MutationAssessor	Pathogenic	3.6	H
PhyloP100	Benign	2.3
popEVE	Benign	-3.6
PrimateAI	Uncertain	0.78	T
PromoterAI	N/A	0.038	Neutral
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Varity_R	N/A	0.98
VESM-3B	Benign	-9.6

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 normal

1 assay found for this variant.

Clinical calibration: 0 functionally abnormal (PS3), 1 functionally normal (BS3).

Protein level

MSH2 LOF scores (HAP1)

MSH2 deep mutational scan

• Gene: MSH2
• Assay type: Cell fitness
• Mechanism: DNA and Mismatch repair
• Model system: Immortalized human cells (Homo sapiens)
• Score: -3.65 · p.His46Gln (assay numbering)

Classified as

BS3 strongFunctionally normalScott calibration: Normal

+4 more calibrations

BS3 strongFunctionally normalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: WT-like

BS3 moderateFunctionally normalIGVF Coding Variant Focus Group -- Controls: All Variants: WT-like

BS3 moderateFunctionally normalRUO ExCALIBR calibration: BS3 Moderate (-2)

BS3 supportingFunctionally normalRUO ExCALIBR calibration (ClinVar 2018): BS3 Supporting (-1)

Other links and lift over

dbSNP: rs33946261;

hg19: chr2-47630468;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar