chr2-47403329-C-G

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-6 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -6 classification points (ACMG Germline Pathogenicity v2019). PP3_ModerateBP6_Very_Strong

The NM_000251.3(MSH2):c.138C>G (p.His46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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) 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 ACMG Germline Pathogenicity v2019

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: Likely_benign. The variant received -6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 3 star(s). ClinVar submissions strongly and reliably favor benignity (20/24 total B/LB).

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