rs2104369996

Variant names:

• chr2-47476401-A-C
• rs2104369996
• NM_000251.3:c.2040A>C
• MSH2 p.Arg680Arg

Your query was ambiguous. Multiple possible variants found:

• chr2-47476401-A-C
• chr2-47476401-A-G
• chr2-47476401-A-T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP6_ModerateBP7

The NM_000251.3(MSH2):c.2040A>C (p.Arg680Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.07
• Publications: 0 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 -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00268) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

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.2040A>C p.Arg680Arg	synonymous	Exon 13 of 16	Prot: NP_000242.1 UniProt:
	MSH2 NM_001406674.1		c.2040A>C p.Arg680Arg	synonymous	Exon 13 of 18	Prot: NP_001393603.1
	MSH2 NM_001406631.1		c.2040A>C p.Arg680Arg	synonymous	Exon 13 of 18	Prot: NP_001393560.1

MSH2 NM_000251.3

MANE Select

HGVSc / HGVSpc.2040A>Cp.Arg680Arg

Exon rankExon 13 of 16

synonymous

Prot: NP_000242.1UniProt: P43246-1

MSH2 NM_001406674.1

HGVSc / HGVSpc.2040A>Cp.Arg680Arg

Exon rankExon 13 of 18

synonymous

Prot: NP_001393603.1

MSH2 NM_001406631.1

HGVSc / HGVSpc.2040A>Cp.Arg680Arg

Exon rankExon 13 of 18

synonymous

Prot: NP_001393560.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MSH2 ENST00000233146.7	TSL:1MANE Select	c.2040A>C p.Arg680Arg	synonymous	Exon 13 of 16	Prot: ENSP00000233146.2 UniProt:
	MSH2 ENST00000406134.5	TSL:1	c.2040A>C p.Arg680Arg	synonymous	Exon 13 of 16	Prot: ENSP00000384199.1 UniProt:
	MSH2 ENST00000918107.1		c.2091A>C p.Arg697Arg	synonymous	Exon 14 of 17	Prot: ENSP00000588166.1 UniProt:

MSH2 ENST00000233146.7

TSL:1MANE Select

HGVSc / HGVSpc.2040A>Cp.Arg680Arg

Exon rankExon 13 of 16

synonymous

Prot: ENSP00000233146.2UniProt: P43246-1

MSH2 ENST00000406134.5

TSL:1

HGVSc / HGVSpc.2040A>Cp.Arg680Arg

Exon rankExon 13 of 16

synonymous

Prot: ENSP00000384199.1UniProt: E9PHA6

MSH2 ENST00000918107.1

HGVSc / HGVSpc.2091A>Cp.Arg697Arg

Exon rankExon 14 of 17

synonymous

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
Local & regional cohorts 1 source Population-specific and national genomic databases
Qatari Genome	AF: 0.00780	AC:1	Hom:	AN:128	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.2
DANN	Benign	0.60
GPN-Star LLR	N/A	-3.8
GPN-Star score	N/A	3.8
Mutation Taster	N/A	97/3	polymorphism
PhyloP100	Benign	-1.1

Showing 8 of 8 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.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2104369996;

hg19: chr2-47703540;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar