rs786202481

Variant names:

• chr2-47482932-A-AT
• rs786202481
• NM_000251.3:c.2789dupT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_000251.3(MSH2):​c.2789dupT​(p.Val932SerfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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. Fraction of 0.00535 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2789dupT	p.Val932SerfsTer21	frameshift_variant	Exon 16 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2789dupT	p.Val932SerfsTer21	frameshift_variant	Exon 16 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33

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: 0.00000402 AC: 1 AN: 248670 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134642

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: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459610 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 725984

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74392

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

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Sep 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 16 of the MSH2 gene, causing a frameshift in the last exon. This results in a protein product that is 17 amino acids longer than the normal protein product. To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/248670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2789dupT variant, located in coding exon 16 of the MSH2 gene, results from a duplication of T at nucleotide position 2789, causing a translational frameshift with a predicted alternate stop codon (p.V932Sfs*21). This alteration occurs at the 3' terminus of the MSH2 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 17 amino acids. This frameshift impacts the last 3amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified Uncertain:1

May 01, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.2789dupT (p.Val932SerfsX21) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4e-06 in 248670 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2789dupT has been reported in the literature in at least one individual affected with breast cancer (example: Bhai_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 185819). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Lynch syndrome 1 Uncertain:1

Aug 18, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Uncertain:1

Nov 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 16 of the MSH2 gene, causing a frameshift in the last exon and addition of 20 new amino acids before introducing a stop codon. This results in a protein product that is 17 amino acids longer than the normal protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/248670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Aug 10, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in the last 3 amino acids being replaced with 20 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); Identified in an individual with a personal history of breast cancer and family history of breast, ovarian, and gastrointestinal cancers (Bhai et al., 2021); This variant is associated with the following publications: (PMID: 9774676, 18822302, 21120944, 27873144, 34326862) -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the MSH2 gene (p.Val932Serfs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the MSH2 protein and extend the protein by 17 additional amino acid residues. This variant is present in population databases (rs786202481, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185819). RNA analysis performed to evaluate the impact of this frameshift on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs786202481; hg19: chr2-47710071;