NM_000251.3:c.2038C>G

Variant names:

• chr2-47476399-C-G
• rs63749932
• NM_000251.3:c.2038C>G
• MSH2 p.Arg680Gly

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+7 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 7 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP3_ModerateBP6

The NM_000251.3(MSH2):c.2038C>G (p.Arg680Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000186 (AC=3) in the gnomAD database across 1,614,004 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000241. 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 (no review stars). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R680P: Pathogenic/Likely_pathogenic (ClinVar VariationId 483690, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R680L: Uncertain_significance (ClinVar VariationId 1021808, 2 stars); p.R680Q: Uncertain_significance (ClinVar VariationId 579393, 2 stars); p.R680= (synonymous): Benign/Likely_benign (ClinVar VariationId 2827538, 2 stars); p.R680= (synonymous): Likely_benign (ClinVar VariationId 2819621, 1 star); p.R680= (synonymous): Likely_benign (ClinVar VariationId 4111043, 1 star)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 5.72
• Publications: 32 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_pathogenic. The variant received 7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 19 pathogenic, 12 benign (OR vs. background: 7.8).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000241 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00268) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R680P: Pathogenic/Likely_pathogenic (ClinVar VariationId 483690, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R680L: Uncertain_significance (ClinVar VariationId 1021808, 2 stars); p.R680Q: Uncertain_significance (ClinVar VariationId 579393, 2 stars); p.R680= (synonymous): Benign/Likely_benign (ClinVar VariationId 2827538, 2 stars); p.R680= (synonymous): Likely_benign (ClinVar VariationId 2819621, 1 star); p.R680= (synonymous): Likely_benign (ClinVar VariationId 4111043, 1 star)
	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 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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.2038C>G p.Arg680Gly	missense	Exon 13 of 16	Prot: NP_000242.1 UniProt:
	MSH2 NM_001406674.1		c.2038C>G p.Arg680Gly	missense	Exon 13 of 18	Prot: NP_001393603.1
	MSH2 NM_001406631.1		c.2038C>G p.Arg680Gly	missense	Exon 13 of 18	Prot: NP_001393560.1

MSH2 NM_000251.3

MANE Select

HGVSc / HGVSpc.2038C>Gp.Arg680Gly

Exon rankExon 13 of 16

missense

Prot: NP_000242.1UniProt: P43246-1

MSH2 NM_001406674.1

HGVSc / HGVSpc.2038C>Gp.Arg680Gly

Exon rankExon 13 of 18

missense

Prot: NP_001393603.1

MSH2 NM_001406631.1

HGVSc / HGVSpc.2038C>Gp.Arg680Gly

Exon rankExon 13 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.2038C>G p.Arg680Gly	missense	Exon 13 of 16	Prot: ENSP00000233146.2 UniProt:
	MSH2 ENST00000406134.5	TSL:1	c.2038C>G p.Arg680Gly	missense	Exon 13 of 16	Prot: ENSP00000384199.1 UniProt:
	MSH2 ENST00000918107.1		c.2089C>G p.Arg697Gly	missense	Exon 14 of 17	Prot: ENSP00000588166.1 UniProt:

MSH2 ENST00000233146.7

TSL:1MANE Select

HGVSc / HGVSpc.2038C>Gp.Arg680Gly

Exon rankExon 13 of 16

missense

Prot: ENSP00000233146.2UniProt: P43246-1

MSH2 ENST00000406134.5

TSL:1

HGVSc / HGVSpc.2038C>Gp.Arg680Gly

Exon rankExon 13 of 16

missense

Prot: ENSP00000384199.1UniProt: E9PHA6

MSH2 ENST00000918107.1

HGVSc / HGVSpc.2089C>Gp.Arg697Gly

Exon rankExon 14 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: 0.00000657	AC:1	Hom:0	AN:152130	Cov:32
GnomAD2 exomes	AF: 0.0000159	AC:4	Hom:	AN:251446	Cov:
GnomAD4 exome Warning	AF: 0.00000137	AC:2	Hom:0	AN:1461874	Cov:32
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152130	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:217698	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.00	0	77306	0.0000144	2	138616

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	1	Lynch syndrome 1 (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	2/98	disease causing
MutationAssessor	Pathogenic	4.9	H
PhyloP100	Uncertain	5.7
popEVE	Benign	-4.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.98
VESM-3B	Benign	-14

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
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: -4.22 · p.Arg680Gly (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: rs63749932;

hg19: chr2-47703538;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar