Genetic Variant NM_000251.3:c.2680dupA (chr2-47482821-C-CA) – ACMG Classification: Pathogenic (12 pts)

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.

PP5

Variant 2-47482821-C-CA is Pathogenic according to our data. Variant chr2-47482821-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 229809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.2680dupA	p.Met894AsnfsTer5	frameshift_variant	Exon 16 of 16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.2680dupA	p.Met894AsnfsTer5	frameshift_variant	Exon 16 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152140

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

3

AN:

251144

Hom.:

0

AF XY:

0.0000147

AC XY:

2

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

7

AN:

1461458

Hom.:

0

Cov.:

31

AF XY:

0.00000825

AC XY:

6

AN XY:

727022

show subpopulations

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152140

Hom.:

0

Cov.:

33

AF XY:

0.0000135

AC XY:

1

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Aug 22, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This duplication of one nucleotide in MSH2 is denoted c.2680dupA at the cDNA level and p.Met894AsnfsX5 (M894NfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACAA[dupA]TGCC. The duplication causes a frameshift which changes a Methionine to an Asparagine at codon 894, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. MSH2 c.2680dupA has been reported in individuals with Lynch syndrome, and mismatch repair immunohistochemistry (MMR IHC) data available on a tumor showed loss of MSH2 and MSH6 in at least one carrier (Casey 2005, Lagerstedt-Robinson 2016). Based on the currently available information, we consider this duplication to be a likely pathogenic variant. -

Jul 18, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome

Pathogenic:2

Aug 01, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2680dup (p.Met894Asnfs*5) variant of the MSH2 gene is located on the last exon and is predicted to create an early stop codon. While this variant is not expected to result in nonsense mediated mRNA decay, it is predicted to disrupt the last 41 amino acids of the MSH2 protein. This variant has been reported in multiple individuals with colorectal cancer, Lynch syndrome, and ovarian cancer (PMID: 15713769, 22949379, 27601186, 28514183, 30077346, 30322717), including one individual with Lynch syndrome and a positive family history (PMID: 30077346). This variant has been identified in 3/251144 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Therefore, the c.2680dup (p.Met894Asnfs*5) variant of the MSH2 gene is classified as likely pathogenic. -

Jul 24, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met894AsnfsX5 variant in MSH2 has been reported in at least 2 individuals with Lynch syndrome associated cancers (Casey 2005 PMID: 15713769, Lagerstedt-Robinson 2016 PMID: 27601186, Carter 2018 PMID: 30322717). In addition, tumors sampled from 1 of these individuals lacked MSH2 and MSH6 expression. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 229809) and has been identified in 0.003% (3/113586) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 894 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the last exon and is therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~4% of the coding region, with 36 amino acids removed. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1_Moderate, PM2, PS4_Supporting, PS3_Moderate. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Oct 13, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2680dupA pathogenic mutation, located in coding exon 16 of the MSH2 gene, results from a duplication of one nucleotide at position c.2680 resulting in a translational frameshift with a predicted alternate stop codon (p.M894Nfs*5). This alteration occurs at the 3' terminus of the MSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 41 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been detected in multiple individuals diagnosed with colorectal cancer that demonstrated either high microsatellite instability (MSI-H) or absent MSH2 and/or MSH6 staining by immunohistochemistry (IHC) (Ambry internal data; Casey G et al. JAMA 2005 Feb; 293(7):799-809). As such, this alteration is interpreted as a disease-causing mutation. -

Aug 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 16 of the MSH2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial, ovarian, and colorectal cancer (PMID: 15713769, 30077346, 30322717, PMID: 35430768; ClinVar SCV000273149.7) and in families with suspected Lynch syndrome (PMID: 27601186). A couple of the individuals affected with colorectal cancer had tumors with either loss of MSH2 and MSH6 protein via immunohistochemistry and/or high microsatellite instability (PMID: 15713769; ClinVar SCV000273149.7). This variant has been identified in 3/251144 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Dec 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.2680dupA (p.Met894AsnfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251144 control chromosomes. c.2680dupA has been reported internally and in the literature in multiple individuals affected with clinical features of Hereditary Nonpolyposis Colorectal Cancer (example, Lagerstedt-Robinson_2016, Labcorp Genetics (formerly Invitae)). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30322717, 15713769, 28514183, 30251116, 27601186, 35430768, 22949379). ClinVar contains an entry for this variant (Variation ID: 229809). Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome 1

Pathogenic:1

Mar 14, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Met894Asnfs*5) in the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the MSH2 protein. This variant is present in population databases (rs756190190, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with clinical features of Lynch syndrome (PMID: 27601186, 28514183, 30322717; external communication). ClinVar contains an entry for this variant (Variation ID: 229809). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -

MSH2-related disorder

Uncertain:1

Nov 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.2680dupA variant is predicted to result in a frameshift and premature protein termination (p.Met894Asnfs*5). This variant has been reported in at least five individuals with Lynch syndrome cancers and an additional individual undergoing Lynch syndrome genetic testing (Table 6. Casey et al. 2005. PubMed ID: 15713769; Table S1, Carter et al. 2018. PubMed ID: 30322717; Table 1, Lagerstedt-Robinson et al. 2016. PubMed ID: 27601186; Table A2, Espenschied et al. 2017. PubMed ID: 28514183; Sup. Material 2, Svensson et al. 2022. PubMed ID: 35430768; Case 1, Bujassoum et al. 2018. J Cancer Sci Ther. 10:9. DOI: 10.4172/1948-5956.1000550). It has also been reported in a mismatch repair deficient Lynch syndrome tumor specimen (Table S2, Henriksson et al. 2019. PubMed ID: 30251116). This variant is reported in 3 of ~251,000 alleles in gnomAD (https://gnomad.broadinstitute.org/variant/2-47709960-C-CA?dataset=gnomad_r2_1). It has conflicting classifications listed in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/229809/). This variant resides in the final exon of this gene, and it is unclear if the resulting mRNA would undergo nonsense-mediated decay. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

NM_000251.3:c.2680dupA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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