chr2-47403193-T-TGGCGGTGCAGCCGAAGGA

Variant names:

• chr2-47403193-T-TGGCGGTGCAGCCGAAGGA
• rs281864943
• NM_000251.3:c.4_21dupGCGGTGCAGCCGAAGGAG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_000251.3(MSH2):​c.4_21dupGCGGTGCAGCCGAAGGAG​(p.Ala2_Glu7dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00000416 in 1,442,386 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T8T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: MSH2 NM_000251.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 6.98
• Publications: 4 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: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000251.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.4_21dupGCGGTGCAGCCGAAGGAG	p.Ala2_Glu7dup	conservative_inframe_insertion	Exon 1 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.4_21dupGCGGTGCAGCCGAAGGAG	p.Ala2_Glu7dup	conservative_inframe_insertion	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000463 AC: 1 AN: 215854 AF XY: 0.00000851

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1442386 Hom.: 0 Cov.: 31 AF XY: 0.00000559 AC XY: 4 AN XY: 715818

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 41458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25682

East Asian (EAS) AF: 0.00 AC: 0 AN: 39018

South Asian (SAS) AF: 0.00 AC: 0 AN: 83256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1104016

Other (OTH) AF: 0.00 AC: 0 AN: 59704

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Dec 22, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This in-frame duplication of 18 nucleotides in MSH2 is denoted c.4_21dup18 at the cDNA level and p.Ala2_Glu7dup (A2_E7dup) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is cATG{dup18}ACGC. The duplicated amino acids are all conserved through species except for the last amino acid, a Glutamic Acid, which is not conserved. This duplication is located in the mismatch binding domain (Lutzen 2008). This variant was reported in an individual with a MSI-High colorectal cancer: however, this tumor was shown to have normal immunohistochemical staining for the Lynch related proteins (Krüger 2003). Since in-frame duplications may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH2 Ala2_Glu7dup to be a variant of uncertain significance. -

May 23, 2017

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: The MSH2 c.4_21dupGCGGTGCAGCCGAAGGAG (p.Ala2_Glu7dup) variant leads to a duplication of six amino acids (AVQPKE) in exon 1. Mutation taster predicts a benign outcome for this variant. This variant was found in 1/37562 control chromosomes including ExAC at a frequency of 0.0000266, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). This variant has been reported in two patients (one with colon cancer not fulfilling Bethesda criteria and another with Lynch Syndrome patient fulfilling modified Bethesda criteria) without strong evidence for or against pathogenicity (Kruger_2003, Mangold_2005). Tumor from one of the patients showed MSH-I but normal expression of MMR proteins (Kruger_2003). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." -

May 28, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2

Jan 27, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a duplication of 6 amino acids within the mismatch binding domain of the MSH2 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer, with the tumor showing high microsatellite instability and normal MLH1/MSH2 expression (PMID: 12655562). This variant has also been reported in an individual suspected of having Lynch syndrome (PMID 15849733). This variant has been identified in 1/215854 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. -

Feb 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4_21dup18 variant, located in coding exon 1 of the MSH2 gene, results from an in-frame duplication of 18 nucleotides between positions 4 to 21, causing the duplication of 6 amino acids. This duplication has been detected in an individual with early-onset colorectal cancer, whose tumor was MSI-H, but showed intact MSH2 and MSH6 staining on IHC (Krüger S, Hum. Mutat. 2003 Apr; 21(4):445-6). This region is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.4_21dup, results in the insertion of 6 amino acid(s) of the MSH2 protein (p.Ala2_Glu7dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752412603, gnomAD 0.001%). This variant has been observed in individual(s) with Lynch syndrome (PMID: 15849733). ClinVar contains an entry for this variant (Variation ID: 91114). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=4/196	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs281864943; hg19: chr2-47630332;